Literature DB >> 32130258

Serum uric acid a depression biomarker.

Xiandong Meng1, Xia Huang1, Wei Deng1, Jiping Li2, Tao Li1.   

Abstract

OBJECTIVE: We aimed to investigate the difference in serum uric acid(SUA)levels between subtypes of depression and normal population, and whether SUA can be used to identify bipolar disorder depressive episode and major depressive disorder and predict the length of hospital stay.
METHODS: 1543 depression patients and 1515 healthy controls were obtained according to the entry and exclusion criteria from one mental health center of a tertiary hospital in southwestern China. The diagnosis and classification of depression was in accordance with ICD-10. The SUA value was derived from fasting plasma samples analysis. The level of SUA of all the participants was quantified using Roche cobas8000-c702-MSB automatic biochemical analyzer. Data were analyzed by SPSS18.0 statistical software package.
RESULTS: Overall, the level of SUA in patients with depression was lower than that in normal control. Specifically, males' SUA levels were in the interval of [240, 323.3) and [323.3, 406.6), and women were in the [160, 233.3] levels. The SUA level of bipolar disorder depressive episode was higher compared to major depressive disorder level. Interestingly, male patients who were hospitalized for two weeks had higher SUA than those who were hospitalized for three weeks or four weeks.
CONCLUSIONS: Our results suggest that the length of hospital stay may be associated with SUA, and when it is difficult to make a differential diagnosis of bipolar disorder depressive episode and major depressive disorder, the level of SUA may be considered. The adjustment of SUA as a method for treating depression needs to be carefully assessed.

Entities:  

Year:  2020        PMID： 32130258      PMCID： PMC7055893          DOI： 10.1371/journal.pone.0229626

Source DB:  PubMed          Journal:  PLoS One        ISSN： 1932-6203            Impact factor:   3.240


Introduction

Depression has a high prevalence and is a heavy disease burden. According to statistics, its global prevalence rate is about 4% to 5% [1], and about 10% to 20% of people have had various types of depression in their lifetime [2,3]. It is predicted that by 2020 [4]depression will rank second in the global burden of disease. Depression is thought to be the result of genetic predisposition combined with environmental interactions, and the oxidative stress may be one of its pathogenesis [5,6]. Oxidative stress can lead to decreased brain neurogenesis and increased neuronal apoptosis [7], and it can affect the activity of 5-HT neurotransmitters and the metabolic pathways of monoamine neurotransmitters [8]. In patients with depression, oxidative stress and lipid per oxidation are enhanced and the total antioxidant capacity is reduced [5,6], which in turn leads to various depressive symptoms in patients. Uric acid is the end product of purine metabolism, which has endogenous or exogenous origin. Endogenous uric acid is produced primarily by the degradation of nucleic acids, adenine, and guanine by normal or impending dying cells. Exogenous uric acid is mainly produced by the synthesis of purine produced by animal proteins in the liver, small intestine, muscle tissue, kidney and vascular endothelium [9,10]. Uric acid is mainly excreted through the kidneys. Increased Serum uric acid (SUA) levels may cause gout, dyslipidemia, cardiovascular disease, high blood pressure, and other physical diseases [11-13]. On the other hand, decreased SUA levels may cause neurodegenerative diseases such as Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, and multiple sclerosis [14-16]. SUA is a strong antioxidant that provides more than 60% antioxidant activity in plasma [17,18]. The major mechanisms of uric acid function have been reported including: maintenance of peroxidase activity, which in turn prevents the formation of superoxide and peroxynitrite [19]; prevention of cellular enzymes in activation caused by peroxynitrite, which can result in damage to the cytoskeleton [20]; and inhibition of iron-dependent ascorbate oxidase by binding to iron, thereby preventing damage caused by oxidative stress [21]. There is no consistent pattern for SUA levels in patients with depression. Studies have shown that SUA in depression can be excessively consumed due to an increase in the anti-oxidative stress, and showed a downward trend [22], however, other studies have found that SUA levels in patients was higher than controls [23]. The reasons for this discrepancy can be associated with several factors; First, in published studies, different diagnostic criteria for depression was used. Currently there are 2widely accepted diagnostic criteria for depression: the International Classification of Diseases-10 (ICD-10) of Mental and Behavioural Disorders, and the Diagnostic and Statistical Manual of Mental Disorders-V (DSM-V). Importantly, both classifications differ greatly in the diagnostic criteria for depression [24]. In addition, depression has a variety of clinical subtypes and SUA may vary in the different subtypes, but previous studies have not considered these parameters. The present study includes patients diagnosed with depression according to ICD-10 diagnostic criteria when they are discharged; it aims to explore the difference of SUA levels between normal control and patients with depression of different subtypes. The feasibility of using SUA as a biomarker of depression is discussed.

Materials and methods

Study design and population

Patient samples were obtained from the Depression Database in the Research Data Management Platform of Mental Health Center of West China Hospital of Sichuan University. The database recorded all the patients of the Mental Health Center of West China Hospital of Sichuan University since 2009. In this study, inpatients diagnosed for recurrent depressive episode, major depressive disorder, depression with anxiety, bipolar disorder depressive episode according to ICD-10between 2015.1.1–2017.12.31 were included. The healthy control samples were derived from the Laboratory Medicine Center of the West China Hospital of Sichuan University between 2017.1.1–2017.12.31. Exclusion criteria are: repeated hospitalization or multiple physical examinations, age less than 18, lack of SUA data, kidney disease (chronic renal failure, nephritis, nephrotic syndrome, etc.), history of taking drugs that can affect SUA, allergic diseases, metabolic diseases (gout, hyperuricemia), pregnancy or lactation and past smoking history. Overall, samples from a total of 1543 patients and 1515healthy control were obtained. Patients were treated with antidepressants or mood stabilizers. Most of the antidepressants used were SSRIs such ascitalopram, escitalopram, paroxetine, sertraline. Others including tricyclic antidepressants, monoamine oxidase inhibitors, and other antidepressants such as Doxepin, Morclobemide, Trazodone and Agomelatine. The most commonly used mood stabilizers were lithium carbonate, sodium valproate and carbamazepine.

Data collections and measures

Demographic characteristics included: gender, age, marriage, ethnicity, education level, length of hospital stay, all data were directly retrieved from the data management platform. SUA data was derived from biochemical examination of blood samples, fasting and empty stomach the day before the blood draw. The specimens were obtained by the nurses of the ward or the medical examination center. The drawing time was about 7:30 in the morning. The blood collection process was completed following a standardized blood specimen collection process developed by the Laboratory Medicine Center of West China Hospital of Sichuan University certified by CPA International. The collected blood samples were sent to the center by the staff of the transfer department within half an hour after the blood collection. The specimens were analyzed by the Roche cobas8000-c702-MSB automatic biochemical analyzer detection system on the same day. The normal values of SUA are considered to be240-490μmol/Land 160–380μmol/L for male and female respectively. The study was approved by the Medical Ethics Committee of West China Hospital of Sichuan University and implemented in accordance with relevant ethical requirements. The authors had access to information that could identify individual participants during or after data collection.

Statistical analysis

The demographic characteristics of the patient group and the normal control group were compared by chi-square test, and the SUA level was compared by independent sample t test. The comparison between the subtype of depression and the normal control group was assessed by analysis of variance and further by LSD (Least Significant Difference) test. Differences in the SUA levels between patients with different hospital length of stays and normal controls were analyzed by analysis of variance and further by LSD test. All of the above analyses used the SPSS18.0 statistical package. The criterion for statistical significance was p < 0.05.

Results and discussion

Baseline characteristics

Patient’s and the normal population’s age concentrated at 18–34 years, The distribution of other age groups in the two groups was basically the same (Table 1). Most of the participants got married and the percentage was 67.1% and 70.3% in normal population and patient population respectively(Table 1). Comparison of demographic characteristics between patient and normal population indicates no significant statistical difference in age(p = 0.137) and marriage (p = 0.532) (Table 1). The majority of the normal population was male (52.8%), while the majority of the patient population was female(69.7%), which was related to women’s increased vulnerability to depression. The difference between the two groups was statistically significant (p<0.001)(Table 1).
Table 1

Comparison of demographic characteristics between patient population and normal population.

itemcategoriesnormalpatientχ2P
n%n%
age18–3445830.244428.83.1560.532
35–4422214.724916.1
45–5428118.530319.6
55–6427718.325916.8
≥6527718.328818.7
gendermale80052.846830.3159.087<0.001
female71547.2107569.7
marriageunmarried33922.430019.45.5190.137
married101767.1108470.3
divorced865.7764.9
widowed734.8835.4

SUA levels between patients and control groups

Comparison of SUA level in the patient and control groups indicates a statistically significant lower levels in the patient group (p<0.001) (Table 2). In view of the large range of SUA reference values, it was necessary to further explore the exact range of SUA difference between the patient group and the normal control. For this purpose, the value of SUA was divided into five intervals as follow: the normal value of uric acid was equally divided into three intervals including [240–323.3), [323.3–406.6) and [406.6–490), below the lower limit of normal(<240) and, above the upper limit (>490) of normal. Comparison with normal controls was analyzed separately for male and female patients (Tables 3 and 4). SUA levels in the male patients and normal population was statistically significant in the [240–323.3) and [323.3–406.6) ranges(p<0.001) however the difference for the female patient and the normal population was only significant in the [160, 233.3] range (p<0.001).
Table 2

Comparison of SUA value between patients and normal.

overallmalefemale
normalpatientnormalpatientnormalpatient
N151515438004687151075
Mean337.47298.54382.81355.24286.73273.86
Sd86.0289.5078.2094.7162.9774.75
t12.2605.3263.929
p<0.001<0.001<0.001
Table 3

Comparison of serum uric acid (SUA) in male between patients and normal.

SUA<240μmol/L240≤SUA<323.3323.3≤SUA<406.6406.6≤SUA≤490SUA>490
normalpatientnormalpatientnormalpatientnormalpatientnormalpatient
n1440171132342179205796736
Mean214.64206.63292.06283.97368.06361.63441.75437.50542.97561.86
Sd21.4727.7022.4123.3024.7722.4722.8122.2049.0891.19
t0.9823.0602.9931.415-1.156
p0.3310.0020.0030.1580.254
Table 4

Comparison of abnormal values of serum uric acid (SUA) in female between patients and normal.

SUA<160μmol/L160≤SUA<233.3233.3≤SUA<306.6306.6≤SUA≤380SUA>380μmol/L
normalpatientnormalpatientnormalpatientnormalpatientnormalpatient
n6391272943474321862224988
Mean141.83141.01212.46204.80269.386267.018336.108338.305432.43434.41
Sd12.1114.6217.6818.9520.136721.038118.972520.515357.6559.06
t0.1323.8801.592-1.122-0.191
p0.896<0.0010.1120.2620.849

SUA between subtypes of depression and normal people

Statistical analysis showed that SUA levels were different between depression subtypes and normal population (p<0.001) (Table 5). Further LSD analysis found that the difference of SUA between the patients with recurrent depressive episode, major depressive disorder, depression with anxiety and normal control was statistically significant (p<0.001). The difference of SUA was not statistically significant between bipolar disorder patients with depressive episode and normal controls (p = 0.223). Interestingly the difference of SUA between bipolar disorder with depressive episode and depressive episode patients was statistically significant (p<0.001).
Table 5

Comparison of SUA between subtypes of depression and normal people.

Subtypes of depressionNMeanSdFP
recurrent depressive episode220287.0183.6844.448<0.001
major depressive disorder1066298.5089.61
depression with anxiety105279.8980.26
bipolar disorder depressive episode152328.4096.05
normal1515337.4786.02

Further LSD test found:

The difference of SUA between the patients with recurrent depressive episode, major depressive disorder, depression with anxiety and normal was statistically significant (p<0.001).

The difference of SUA was not statistically significant between the patients with bipolar disorder depressive episode and normal (p = 0.223).

The difference of SUA between patients with bipolar disorder depressive episode and major depressive disorder was statistically significant (p<0.001).

Further LSD test found: The difference of SUA between the patients with recurrent depressive episode, major depressive disorder, depression with anxiety and normal was statistically significant (p<0.001). The difference of SUA was not statistically significant between the patients with bipolar disorder depressive episode and normal (p = 0.223). The difference of SUA between patients with bipolar disorder depressive episode and major depressive disorder was statistically significant (p<0.001).

SUA between patients with different length of hospitalization and normal people

Statistical analysis showed that there was a statistically significant difference in SUA levels between patients’ different hospital stays and normal population (p<0.001) (Table 6). Furthermore, LSD test found that among male, the difference of SUA between two and three weeks (p = 0.023) and between two and four weeks (p = 0.005)of hospitalization were statistically significant. However the difference between three weeks and four weeks of hospitalization was not statistically significant (p = 0.424). Among female, there was no statistically significant difference in SUA between patients with the different length of hospital stays (p>0.05).
Table 6

Comparison of SUA between patients with different hospital stay* and normal people.

malefemale
two weeksthree weeksfour weeksnormaltwo weeksthree weeksfour weeksnormal
N136163112800311408231715
Mean371.13348.93340.66382.81269.12273.33278.72286.73
Sd96.999.4585.0278.267.7376.8171.6562.97
F13.5896.098
P<0.001<0.001

Further LSD test found:

Among male, the difference of SUA between the two weeks of hospitalization and the three weeks was statistically significant(p = 0.023). The difference of SUA between the two weeks of hospitalization and four weeks of hospitalization was also statistically significant (p = 0.005). The difference between the three weeks of hospitalization and the four weeks of hospitalization was not statistically significant (p = 0.424).

Among female, there was no statistically significant difference in SUA between patients with different hospital stays (p>0.05).

*Patients hospitalized for one week or longer than four weeks were excluded from statistical analysis, cause of the too small sample size.

Further LSD test found: Among male, the difference of SUA between the two weeks of hospitalization and the three weeks was statistically significant(p = 0.023). The difference of SUA between the two weeks of hospitalization and four weeks of hospitalization was also statistically significant (p = 0.005). The difference between the three weeks of hospitalization and the four weeks of hospitalization was not statistically significant (p = 0.424). Among female, there was no statistically significant difference in SUA between patients with different hospital stays (p>0.05). *Patients hospitalized for one week or longer than four weeks were excluded from statistical analysis, cause of the too small sample size.

Discussion

Epidemiological data suggest that depression has a higher prevalence and morbidity in women. Indeed, the incidence in female is about twice than that in men [25,26]. The present study sampling method is based on the established inclusion and exclusion criteria. A total of 1,543 patients composed of1075 females and 468 males were analyzed, this represents a ratio of 2.3(Table 1). Interestingly this corroborates with reported epidemiological data, indicating that our sample population was representative. Given the difference in the reference values of SUA between female and male genders and the gender composition ratio within the patient groups, the study was stratified by gender, followed by analysis of SUA levels. Oxidative stress is one of depression pathogenesis. Excessive oxidative stress leads to impaired brain function in patients, leading to various psychiatric symptoms. SUA is a strong antioxidant [27] and is constantly consumed to counterattack the oxidative stress. This study showed that SUA level in depression and normal control group was different and statistically significant (p<0.001), and that the level in patients with depression was lower than that in normal people (Table 2). This finding is consistent with previous research reports. It confirms the role of oxidative stress in the pathogenesis of depression, and also suggests that SUA levels can be used as a biomarker for depression. Because SUA is excessively consumed, the antioxidant function in the brain is reduced leading to the onset of the disease. Therefore, adjusting the SUA level in patients might restore the ability of antioxidant stress and protect the brain function in patients with depression. Given the wide range of normal SUA values, it is worth exploring further the utility of this marker. The present study analyzed the results based on 5 intervals ranges of normal SUA and according to genders. The statistical analysis showed that the difference in SUA levels between the male patient group and the normal control group was statistically significant in two 2 SUA level interval ranges: the [240, 323.3) and [323.3, 406.6) (p<0.001) (Table 3). Whereas the difference in SUA levels between the female patient group and the normal control group was statistically significant in the [160, 233.3) interval (p<0.001) (Table 4). These type of analysis and findings have not been mentioned in previous studies. This result indicates that SUA levels in patients with depression show differences compared to normal population only within a specific narrow range of SUA levels. This type of analysis should be taken in consideration when using SUA as a biomarker for depression, even though it was significant only in a small part of the patients. This finding also indicate the importance of identifying additional biological markers for depression. In recent years, modulation of SUA level was thought to represent a novel target for affective disorder treatment [28,29]. Although elevated SUA levels may have a protective effect on the central nervous system and may reduce the incidence of depression, on another hand high SUA levels can lead to increased morbidity and mortality due to several pathologies including hypertension, gout, coronary heart disease, stroke and other diseases induced by excessive SUA level. Therefore, the ideal level of SUA should be able to procure central nervous system protection while reducing the risk of inducing other diseases [30]. If the regulation of SUA levels is used as a treatment for depression, then the possible effect of SUA on the other potential diseases should be taken into account and the benefit for patients should be weighed instead of blindly regulating this marker by diet or medication, The current antioxidant treatments, whether given in prophylactic or therapeutic setting, are not always beneficial and can be harmful for human health [31]. According to this study findings, if the adjustment of SUA level would be used as a treatment for depression, it is recommended to intervene only within patients having circulating SUA levels within the lower normal range. As per ICD-10 diagnostic criteria, depression includes multiple subtypes, and the differences in SUA levels between the normal populations and the disease subtypes have been less studied in previous studies. The present study found that the difference between SUA in patients with recurrent depressive episode, major depressive disorder, depression with anxiety compared to normal control was statistically significant (p<0.001) (Table 5). This is consistent with previous reports, but the difference of SUA between patients with bipolar disorder depressive episode and normal controls was not statistically significant (p = 0.223) (Table 5). Previous studies showed that SUA production was increased in mania patients due to the dysfunction of purinergic system, and the SUA levels were higher than normal [32,33]. Patients with depression have an increased SUA consumption due to oxidative stress [22] which in turn shows lower levels of SUA compared to normal population [34,35]. There is no difference in SUA between bipolar disorder depressive episode and normal populations. One explanation for this later finding is that the production and the consumption of SUA might occur at the same time, in order to maintain a balance. Based on this, we could assume that when the production of SUA is higher than the consumption, the symptom of mania will display more, and when the production of SUA is lower than the consumption, it’s the symptom of depression that will show more in bipolar disorder depressive episode patients. This advanced hypothesis requires further research. The difference of SUA between patients with bipolar disorder depressive episode and major depressive disorder was statistically significant (p<0.001)(Table 5). According to this result, It could be hypothesized that SUA may be a biomarker for the differentiation of unipolar and bipolar affective disorder. In outpatients and inpatients, as well as in children and adolescents, bipolar disorder with depressive episodes is often misdiagnosed as major depressive episodes [36]. This is due to the doctor’s personal interpretation of the diagnostic criteria and symptom description given the patients. In addition, the absence of biomarker for reference makes it difficult to make the right diagnosis which increases the ambiguity in making the right diagnosis. It is necessary to do more researches to further show the specific efficacy of SUA as a biomarker for distinguishing these two diseases in future. Hospitalization is an important part for treatment of acute depression. The length of hospital stay is directly correlated to the severity of the illness. The results showed that among male, the difference of SUA between the two weeks of hospitalization and three weeks (p = 0.023) and between two and five weeks (p<0.001) was statistically significant (Table 5). In general, patients with mild illnesses have shorter hospital stays, and those with severe illnesses have longer hospital stays. The SUA level in male patients who were hospitalized for two weeks was higher than in those hospitalized for three or four weeks, indicating that SUA was more consumed as the condition worsened. The average hospitalization day is currently the focus of government, patients and medical institutions. How to better predict the hospitalization time of patients is a problem worth exploring, however it lacks objective monitoring parameters, according to the result of this study, SUA level may be considered. This study presents several limitations. First, it’s a single-center study, mainly involving Han nationality patients; however given that China is a multi-ethnic country with a large population, it’s impossible to have a nation-wide representative population. Secondly, the current research included a single biomarker. For a more comprehensive analysis, identifications of additional biomarkers warrant consideration. Furthermore, this study used patient hospital discharge diagnosis to identify the target population; however the patient population was treated by different doctors within the same hospital. The diagnosis of depression and depression subtypes might be different between different doctors, and this might affect the overall research results. It will be interesting the run the same study with patients’ samples from same center and treated with same doctor.

Conclusions

Overall, our analysis showed that SUA level in patients with depression is lower than that in normal population, but this difference is mainly reflected in the lower level of normal SUA value. This finding should be considered by the medical staff treating patients. The length of hospital stay may be associated with SUA, and when it is difficult to make a differential diagnosis of bipolar disorder depressive episode and major depressive disorder, the level of SUA may be considered. Although we can’t draw the conclusion that SUA is a biomarker of depression according to the present results, it has certain reference value for subsequent related researches.

Data used in this study.

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(Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: The authors examined the difference in serum uric acid levels between depression and normal population in a large cohort, and they demonstrated that the levels of serum uric acid was lower than that in normal control, as well as higher serum uric acid levels in bipolar depressive episode compared to major depressive disorder. Furthermore, they demonstrated higher serum uric acid levels in male patients who were hospitalized for two weeks than in those who were hospitalized for three weeks or four weeks. This study is interesting, and this study includes positive findings. I wrote several comments below. 1. In methods, they should write how to treat the blood in detail (drawing time, processing and storage conditions). 2. In methods, there are no information of patient`s medication, such as antidepressants or mood stabilizers). 3. In methods; how to evaluate non-psychiatric controls? 4. In methods; they wrote that they exclude repeated hospitalization. Did all patients who participated in this study admit first time? Please write this exactly. 5. In results; did raw serum uric concentration values did follow a Gaussian distribution? If not, the data should be natural log-transformed before the analysis. 6. In results and discussion; they often wrote that SUA can be used as a biomarker for depression. Although they showed that the levels of serum uric acid was lower than that in normal control, as well as higher serum uric acid levels in bipolar depressive episode compared to major depressive disorder, they did not show the usefulness of biomarkers. They should show a sensitivity and specificity. 7. In conclusion, they wrote that SUA can be biological marker to predict the severity of the disease. However, they did not show the severity of patients and treatments in this study. I think this conclusion is not proper. 8. In limitations, it is better to write that the differences in serum uric acid levels between bipolar depressive episode and major depressive disorder may reflect different treatments between them (not reflect different diagnosis). Reviewer #2: The authors investigated the difference in serum uric acid concentration between subtypes of depression and normal population in a cohort comprising 1543 depression patients and 1515 healthy controls. They further analysed whether serum uric acid can be used to identify bipolar disorder depressive episode and major depressive disorder and also asked the question if it can be used as a biomarker to predict the length of hospital stay. They found lower concentrations of uric acid in patients with depression compared to the controls and higher concentrations in patients with bipolar disorder depressive episodes compared to patients with major depressive disorder. The research question is interesting but I have several concerns: - The differences in uric acid concentrations seem to be rather small even in those groups where the difference is statistically significant. The authors categorized the patients according to their uric acid concentration in five groups and then perform five t tests. I wonder if an adjustment for multiple testing would be appropriate here. Anyway, are the differences in uric acid concentrations clinically meaningful? How large is the overlap in the uric acid distributions between the cases and the controls? - Was it really one of the aims to analyse uric acid as a biomarker for hospital stay? Or was this only added because the p value was significant? I would not present this result so prominently because I do not see the use of it. - It would be a large improvement if the authors could replicate their findings in another study but I am aware of the fact that this might be difficult to accomplish. - Patients with hyperuricemia have been excluded from the study. How many patients with depression also suffer from hyperuricemia? - Do the authors have any information on other markers of oxidative stress? - Only very few characteristics of the study population are presented and possible confounding cannot be assessed. Is information regarding inflammation markers of e.g. coronary heart disease available? Depression and coronary heart disease might be linked vi inflammation or one may increase the risk of developing the other. - The authors first state that “all data are fully available without restriction” but then state that “Data cannot be shared publicly because of the request of our hospital”. So I think the first statement will have to be changed. - There are some typos and repeatedly whitespaces are missing. The language should be revised. The unit of uric acid is given as umol//L instead of µmol/L. - In all the tables as well as in the text a number of p values is reported as 0.00. I would recommend to report three digits. Please report the actual p value and use something like p<0.001 for very low p values. - Table 1 is not referenced in the text. - Why did the authors categorize age? They could use it as continuous variable. - Was uric acid normally distributed? It would be interesting to look at the distribution in the different patient groups, perhaps in form of box plots. Reviewer #3: The manuscript described a technically sound piece of scientific research with data that supports the conclusions. and the experiments have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions have drawn appropriately based on the data presented. The manuscript is technically sound, and the data support the conclusions. But the authors have not made all data underlying the findings in their manuscript fully available. ********** 6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: Yes: Shusuke Numata Reviewer #2: No Reviewer #3: No [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step. 21 Jan 2020 PONE-D-19-30310 Serum uric acid a depression biomarker PLOS ONE Dear Mr. Meng, Thank you for submitting your manuscript to PLOS ONE. 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I downloaded the style templates from the website above and amended my manuscript (see pages in the Revised Manuscript with Track Changes) 2. Thank you for stating the following beneath the Acknowledgments Section of your manuscript Funding Financial support for this research was from Ministry of Science and Technology of People's Republic of China (National key research and development plan). Name of the project is study on the precise diagnosis and treatment model of schizophrenia based on multi-omics map, and the item number is 2016YFC0904300. We note that you have provided funding information that is not currently declared in your Funding Statement. However, funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form. Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows: "The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. a. Please provide an amended Funding Statement that declares *all* the funding or sources of support received during this specific study (whether external or internal to your organization) as detailed online in our guide for authors at http://journals.plos.org/plosone/s/submit-now b. Please state what role the funders took in the study. If any authors received a salary from any of your funders, please state which authors and which funder. If the funders had no role, please state: "The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript." c. c. 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We will update your Data Availability statement on your behalf to reflect the information you provide. Reply Amended. At the time of submission, we did not fully understand the requirements for data upload. After consulting our hospital's management agency, the data used in this study can be uploaded. We have uploaded the data while uploading the revised manuscript and noted this in the cover letter. 4. We note you have included a table to which you do not refer in the text of your manuscript. Please ensure that you refer to Table 1 in your text; if accepted, production will need this reference to link the reader to the Table. Reply Amended (see page5 in the Revised Manuscript with Track Changes) 5. Please include your tables as part of your main manuscript and remove the individual files. Please note that supplementary tables should be uploaded as separate "supporting information" files. Reply Amended (see page5-6 in the Revised Manuscript with Track Changes) 6. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information [Note: HTML markup is below. Please do not edit.] Reply Amended (see page12 in the Revised Manuscript with Track Changes) Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: No Reviewer #2: Partly Reviewer #3: Yes________________________________________ 2. 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Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: No Reviewer #3: Yes ________________________________________ 5. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: The authors examined the difference in serum uric acid levels between depression and normal population in a large cohort, and they demonstrated that the levels of serum uric acid was lower than that in normal control, as well as higher serum uric acid levels in bipolar depressive episode compared to major depressive disorder. Furthermore, they demonstrated higher serum uric acid levels in male patients who were hospitalized for two weeks than in those who were hospitalized for three weeks or four weeks. This study is interesting, and this study includes positive findings. I wrote several comments below. 1. In methods, they should write how to treat the blood in detail (drawing time, processing and storage conditions). Reply Amended (see page4 in the Revised Manuscript with Track Changes) 2. In methods, there are no information of patient`s medication, such as antidepressants or mood stabilizers). Reply Amended (see page3 in the Revised Manuscript with Track Changes) 3. In methods; how to evaluate non-psychiatric controls? Reply The non-psychiatric control group in this study was derived from the physical examination population in our hospital. Before the physical examination personal information registration was required, including personal past history, present history, and family history. In view of the possible stigma of patients with psychiatrics, there are two cases of the authenticity of the medical history information provided by the population. One is to provide a completely true history of the individual's psychiatric illness, and the other is to conceal the individual's history of the mental illness. When we designed the study, two different methods were used to solve it. For the former, they were excluded based on the records in the personal information registration form. For the latter, this study did not find a better solution except including them. The reasons are as follows: 1. Patient’s information sharing between medical institutions in China has not yet been realized, so it is impossible for us to know the patient's medical records in other medical institutions. 2. Illness is a patient's privacy. If the person seeking for medical examination is unwilling to provide it, the medical institution has no right to investigate further. But according to our experience we supposed that the person deliberately concealing their past and present history were very few, and for prudence, we consulted a statistician he supposed that the impact on the final study results was very small. 4. In methods; they wrote that they exclude repeated hospitalization. Did all patients who participated in this study admit first time? Please write this exactly. Reply The inpatient information system used by our hospital can record the number of hospitalizations of each patient. According to this, for patients with only one record were selected, and for patients with several records only the relevant data for the first record were selected, but this did not guarantee that all patients included in this study would be their first hospitalization. The reasons are as follows: 1. The source of the data used in this research derived from the inpatient information system of our hospital. Before the system was used, our hospital used the paper version of the disease records. Therefore, the first hospitalized patient recorded in the information system may have been hospitalized in our hospital before. 2. China's hospitalization information for patients has not been shared between medical institutions. Patients may have been hospitalized in other hospitals before coming to our hospital for the first time. 5. In results; did raw serum uric concentration values did follow a Gaussian distribution? If not, the data should be natural log-transformed before the analysis. Reply The histogram and P-P chart were used to judge the distribution of the uric acid value. According to the result, the values followed the Gaussian distribution.(Figure 1-2) Figure 1 P-P diagram and histogram of uric acid distribution in normal population Figure 2 P-P diagram and histogram of uric acid distribution in patients 6. In results and discussion; they often wrote that SUA can be used as a biomarker for depression. Although they showed that the levels of serum uric acid was lower than that in normal control, as well as higher serum uric acid levels in bipolar depressive episode compared to major depressive disorder, they did not show the usefulness of biomarkers. They should show a sensitivity and specificity. Reply In results and discussion, the discussion of serum uric acid as a biological marker that distinguishes bipolar disorder depressive episode and major depressive disorder is indeed not deep enough. This is mainly related to the purpose of this study. Through the current design of this study, only preliminary discovery of serum uric acid may be a biological marker that distinguishes the two diseases. To assist clinical diagnosis, a large sample survey and relevant statistical analysis are needed to clarify the serum uric acid reference and the sensitivity and specificity of these two types of patients. After that the value of serum uric acid may help clinicians to better distinguish the two diseases based on the patient's symptoms and serum uric acid level. These will be the focus of our next research. 7. In conclusion, they wrote that SUA can be biological marker to predict the severity of the disease. However, they did not show the severity of patients and treatments in this study. I think this conclusion is not proper. Reply The judgment of the severity of the patients in this study was based on the length of the patient's hospitalization. According to the principle of diagnosis and treatment, the clinician will continuously evaluate the patient's condition dynamically during the hospitalization. Therefore, the length of hospital stay can indirectly reflect the severity of the patient's condition. Generally speaking, patients with less severe illnesses have shorter hospital stays, and patients with more severe illnesses have longer hospital stays. Therefore, this study combined the differences in uric acid levels between patients with different lengths of hospital stay, and concluded that uric acid uric acid may be a biological indicator reflecting the severity of the patient's illness. 8. In limitations, it is better to write that the differences in serum uric acid levels between bipolar depressive episode and major depressive disorder may reflect different treatments between them (not reflect different diagnosis). Reply The uric acid data of patients in this study were obtained from blood specimens collected on the day of admission or the day after admission. At this time the patient did not receive treatment or the patient's medication has just begun. Therefore, we thought that the difference in uric acid levels between the bipolar disorder depressive episode and major depressive disorder at this time reflected the difference between the two diseases. Therefore, we have concluded that uric acid can be used as a reference for the differential diagnosis of these two diseases. Reviewer #2: The authors investigated the difference in serum uric acid concentration between subtypes of depression and normal population in a cohort comprising 1543 depression patients and 1515 healthy controls. They further analysed whether serum uric acid can be used to identify bipolar disorder depressive episode and major depressive disorder and also asked the question if it can be used as a biomarker to predict the length of hospital stay. They found lower concentrations of uric acid in patients with depression compared to the controls and higher concentrations in patients with bipolar disorder depressive episodes compared to patients with major depressive disorder. The research question is interesting but I have several concerns: - The differences in uric acid concentrations seem to be rather small even in those groups where the difference is statistically significant. The authors categorized the patients according to their uric acid concentration in five groups and then perform five t tests. I wonder if an adjustment for multiple testing would be appropriate here. Anyway, are the differences in uric acid concentrations clinically meaningful? How large is the overlap in the uric acid distributions between the cases and the controls? Reply From the overall comparison of the uric acid level between the normal and patient populations, the difference was statistically significant (see Table 2). Combined with previous research literature, the difference between the two groups, and clinician recommendations, we comprehensively consider the difference had clinical meaning, so the results of this statistical analysis were presented in the final paper. In view of the large range of uric acid reference values, previous studies have failed to determine the specific range of differences in uric acid values between the normal population and depression patients, so this study segmented them based on uric acid reference values and uric acid abnormality values, and finally the specific interval of the difference in uric acid value between the normal population and depression patients. Statistical analysis showed that after subdividing the uric acid value interval, the difference of the uric acid value between the normal population and the depression patient population was statistically significant. Although the value of the difference was small, the results of this study have explored the role of uric acid in the pathogenesis of depression. This may have certain clinical meaning. - Was it really one of the aims to analyze uric acid as a biomarker for hospital stay? Or was this only added because the p value was significant? I would not present this result so prominently because I do not see the use of it. Reply The length of hospital stay is a focus of the society, the government, and medical institutions. Shortening the length of hospitalization is of great significance for reducing the burden of hospitalization for patients and the expenditure of government medical insurance. At present, medical staff's assessment of the expected length of stay of newly admitted patients is mainly based on personal experience and information obtained through interviews, physical examinations and medical history collection. This practice has certain shortcomings. If some kind of biological marker can be used as a reference, it is likely to improve the accuracy of prediction. So we considered it at the beginning of the study design. The reason for linking them was that, according to our clinical observation, the length of hospital stay of patients with severe depression was longer than that of patients with less severe illness. Based on the role of oxidative and antioxidant stress in the pathogenesis of depression, we speculated that patients with long hospital stays may have lower uric acid levels than those with short hospital stays. We therefore included the length of hospital stay and analyzed its relationship with uric acid. We only got the preliminary conclusions, which needed further verification in the future. - It would be a large improvement if the authors could replicate their findings in another study but I am aware of the fact that this might be difficult to accomplish. Reply As pointed out by reviewing experts, there were some shortcomings in this study indeed, but after consulting clinicians and statisticians, we believed that these existing shortcomings would not have a fatal impact on the final research results. If possible, we will carry out one more rigorous designed study in conjunction with valuable suggestions from reviewers, and conduct a more comprehensive and in-depth verification of the research results. - Patients with hyperuricemia have been excluded from the study. How many patients with depression also suffer from hyperuricemia? Reply The hyperuricemia in this study referred to patients who had been explicitly diagnosed with the disease in their past history at the time of admission. For those who had the first uric acid test result after hospitalization that was above the upper limit of normal value and reached the definition of uric acid level for hyperuricemia were included in this study and analyzed as a separate group (see Table 3-4). In this study, 26 patients were explicitly diagnosed to have hyperuricemia. - Do the authors have any information on other markers of oxidative stress? Reply According to the results of the previous literature review and the supplementary review of the literature after obtaining this recommendation, the oxidative stress-related markers in patients with depression are arranged as follows: (1) Malondialdehyde MDA is the final decomposition product of the oxidation reaction of polyvalent unsaturated fatty acids in the body, which will cause cross-linking between DNA molecules, and also cause internal cross-linking of protein molecules to affect the quality and quantity of enzyme proteins, leading to changes in biofilm structure and increased permeability causing cell damage. Its content reflects the level of free radicals in the tissue and the degree of lipid peroxidation [1]. Significant increases in plasma malondialdehyde levels have been reported in patients with depression [2,3]. (2) Inflammatory cytokines Studies have shown that although there is no widespread immune activation in patients with depression, but with the clinical symptoms of depression, the levels of pro-inflammatory cytokines such as IL-1β, IL-6 and TNFα increase in the blood [4]. After antidepressant treatment, the above indicators showed a downward trend, suggesting that these inflammatory factors may be indicators of the state of depression [5]. (3) Cyclooxygenase Cyclooxygenase mainly catalyzes arachidonic acid to produce prostaglandins. Under stress, the expression of cyclooxygenase is significantly enhanced and it is involved in the regulation of inflammatory responses in many tissues. These reactions involve the occurrence and development of neuropsychiatric disorders such as depression and Alzheimer's disease [6,7]. (4) Active nitrogen Nitric oxide has a neurotransmitter or modulatory effect. It transmits information between cells and regulates many behavioral and endocrine responses. But too much nitric oxide release is neurotoxic, leading to hippocampus damage and may play an important role in the pathogenesis of depression [8]. (5) Oxygen free radical Excessive oxygen free radical can damage mitochondrial respiratory chain activity and mitochondrial DNA structure, and then reduce intracellular ATP synthesis, eventually causing mitochondrial permeability change, and a large amount of oxidative active substances released, the latter directly attack cell biological macromolecules, causing cell oxidative damage. Oxidative stress and mitochondrial dysfunction play important roles in the pathogenesis of depression [9,10]. [1] Niki E , Yoshida Y , Saito Y , et al. Lipid peroxidation: Mechanisms, inhibition, and biological effects[J]. Biochemical & Biophysical Research Communications, 2005, 338(1):0-676. [2] Sarandol A , Sarandol E , Eker S S , et al. Major depressive disorder is accompanied with oxidative stress: short-term antidepressant treatment does not alter oxidative-antioxidative systems [J]. Human Psychopharmacology: Clinical and Experimental, 2007, 22(2):67-73. [3] Lipid peroxidation and antioxidant protection in patients during acute depressive episodes and in remission after fluoxetine treatment [J]. Pharmacological Reports, 2009, 61(3):436-447. [4] Goshen I , Kreisel T , Ben-Menachem-Zidon O , et al. Brain interleukin-1 mediates chronic stress-induced depression in mice via adrenocortical activation and hippocampal neurogenesis suppression[J]. Molecular Psychiatry, 2008, 13(7):717-728. [5] Olga J.G. Schiepers, Marieke C. Wichers Cytokines and major depression[J]. Progress in Neuro Psychopharmacology & Biological Psychiatry 2005,29(2):201–217. [6] Black P H . Stress and the inflammatory response: A review of neurogenic inflammation [J]. Brain Behavior and Immunity, 2002, 16(6):0-653. [7] Choi D K , Koppula S , Choi M , et al. Recent developments in the inhibitors of neuroinflammation and neurodegeneration: inflammatory oxidative enzymes as a drug target[J]. Expert Opinion on Therapeutic Patents, 2010, 20(11):1531-1546. [8] Brocardo P S , Budni J , Kaster M P , et al. P.2.d.019 Antidepressant-like effect of the acute administration of folic acid in mice[J]. European Neuropsychopharmacology, 2006, 16(06):S343-S343. [9] Rezin G T , Cardoso M R , Cinara L Gonçalves, et al. Inhibition of mitochondrial respiratory chain in brain of rats subjected to an experimental model of depression[J]. Neurochemistry International, 2008, 53(6-8):395-400. [10] Gong Y , Chai Y , Ding J H , et al. Chronic mild stress damages mitochondrial ultrastructure and function in mouse brain[J]. Neuroscience Letters, 2010, 488(1):76-80. - Only very few characteristics of the study population are presented and possible confounding cannot be assessed. Is information regarding inflammation markers of e.g. coronary heart disease available? Depression and coronary heart disease might be linked vi inflammation or one may increase the risk of developing the other. Reply The existing demographic characteristics were relatively small. Currently, only age, gender, and marriage included. But education, ethnicity, and ethnicity weren’t included. The reason for this is mainly related to the source of the control group selected in this study. The normal control group in this study was derived from the physical examination population in our hospital. (1) Researchers have not been able to obtain the education level information of medical examiners in the electronic information management system of the physical examination crowd. (2) The researchers included ethnic groups in the analysis of the data, but found that most of the ethnic groups studied were Han ethnic groups, and very few were ethnic minorities. Therefore, no special comparative analysis was performed on them. The information was ultimately not presented in the research results. (3) The patients diagnosed and treated by our medical institution are basically yellow races, and other races are basically non-existent, and the current patient information electronic record system of our hospital uses a text format when recording this information. For this reason, the demographic characteristics of race are not presented separately in the study results. During the design phase of this study, we considered the possible impact of the lack of demographic characteristics on the final results, so we consulted a statistical expert. He thought that our concerns were justified, but combined with the reasons we mentioned above, and considering that this study was a large sample study, it was believed that a small demographic feature will have an impact, but it should not be enough to change the final results of the study. After discussion by the research team, finally decided not to include the above demographic characteristics in the analysis. We will try our best to pay attention to the suggestions of reviewers when we do similar researches in the future. The question of whether there are indicators of inflammatory markers for certain diseases such as coronary heart disease. We did not consider it during the study design and implementation stages, mainly because the uric acid involved in this study was not related to inflammatory markers of various diseases. However, during the data collection stage, the past history of patients was included, and some of them did have various chronic physical diseases. - The authors first state that “all data are fully available without restriction” but then state that “Data cannot be shared publicly because of the request of our hospital”. So I think the first statement will have to be changed. Reply Amended and the data will be uploaded with the revised manuscript. - There are some typos and repeatedly whitespaces are missing. The language should be revised. The unit of uric acid is given as umol//L instead of µmol/L. Reply Amended (see pages in the Revised Manuscript with Track Changes) - In all the tables as well as in the text a number of p values is reported as 0.00. I would recommend to report three digits. Please report the actual p value and use something like p<0.001 for very low p values. Reply Amended (see pages in the Revised Manuscript with Track Changes) - Table 1 is not referenced in the text. Reply Amended (see page5 in the Revised Manuscript with Track Changes) - Why did the authors categorize age? They could use it as continuous variable. Reply Age was only used to analyze whether there was a statistical difference between the normal population and the patient population in the study (Table 1). It wasn’t included in the relevant statistical analysis of uric acid as a biological marker of depression. Generally speaking, to facilitate the description of age, it was categorized. At the same time, researchers have also referred to the description of age in the papers published by international journals. Finally, we decided to categorize age. - Was uric acid normally distributed? It would be interesting to look at the distribution in the different patient groups, perhaps in form of box plots. Reply The histogram and P-P chart were used to judge the distribution of the uric acid value. According to the result, the values followed the normal distribution.(Figure 1) Figure 1 P-P diagram and histogram of uric acid distribution in patients Reviewer #3: The manuscript described a technically sound piece of scientific research with data that supports the conclusions. and the experiments have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions have drawn appropriately based on the data presented. The manuscript is technically sound, and the data support the conclusions. But the authors have not made all data underlying the findings in their manuscript fully available. Reply Amended. At the time of submission, we did not fully understand the requirements for data upload. After consulting our hospital's management agency, the data used in this study can be uploaded. We have uploaded the data while uploading the revised manuscript and noted this in the cover letter. ________________________________________ 6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: Yes: Shusuke Numata Reviewer #2: No Reviewer #3: No [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.] Reply I agree to publish the peer review history of their article, and want my identity to be public for this peer review. While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step. Reply There are no figures in this article. Submitted filename: Response to Reviewers.docx Click here for additional data file. 5 Feb 2020 PONE-D-19-30310R1 Serum Uric Acid a Depression Biomarker PLOS ONE Dear Mr. Meng, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. The reviewer #1 addressed minor concerns about your manuscript. Please revise the manuscript again. We would appreciate receiving your revised manuscript by Mar 21 2020 11:59PM. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols Please include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). This letter should be uploaded as separate file and labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'. Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out. We look forward to receiving your revised manuscript. Kind regards, Kenji Hashimoto, PhD Academic Editor PLOS ONE [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #1: All comments have been addressed Reviewer #2: All comments have been addressed ********** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Partly Reviewer #2: Yes ********** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes ********** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #2: Yes ********** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes ********** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: I think that it is too strong to mention that SUA can be used as a biomarker for the differential diagnosis of some subtypes of depression and to determine the length of hospital stay. If the authors will not show specific efficacy of ureic acid as a biological marker in thier draft, the comments in their conclusion should be changed (ex. SUA levels of bipolar disorder depressive episode may be higher compared to major depressive disorder levels, and the length of hospital stay may be associated with serum uric acid levels.). Reviewer #2: (No Response) ********** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: Yes: Numata Shusuke Reviewer #2: No [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step. 8 Feb 2020 Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #1: All comments have been addressed Reviewer #2: All comments have been addressed ________________________________________ 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Partly Reply Amended. The reviewer pointed that the conclusion that serum uric acid was a biological marker of depression was somewhat inadequate based on the results of the current study. In this regard, after discussion by the research team, we adopted the recommendations of the reviewer and partially modified the research conclusions. (page1 and page9) Reviewer #2: Yes ________________________________________ 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes ________________________________________ 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #2: Yes ________________________________________ 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes ________________________________________ 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: I think that it is too strong to mention that SUA can be used as a biomarker for the differential diagnosis of some subtypes of depression and to determine the length of hospital stay. If the authors will not show specific efficacy of ureic acid as a biological marker in thier draft, the comments in their conclusion should be changed (ex. SUA levels of bipolar disorder depressive episode may be higher compared to major depressive disorder levels, and the length of hospital stay may be associated with serum uric acid levels.). Reply Amended. After discussion by the research team, we adopted the recommendations of the reviewer and partially modified the research conclusions. (Page1,Page8,and Page9) Reviewer #2: (No Response) ________________________________________ 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: Yes: Numata Shusuke Reviewer #2: No [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step. Reply The researcher logged on the website you mentioned above, and entered the relevant interface after registration, but found that the website only edits figures, and the results of this study were presented in tables, so the research team believes that we needn’t do this. We are not quite sure whether our understanding is correct. If we understand incorrectly, we hope you give us the opportunity to make changes. Submitted filename: Response to reviewers1.docx Click here for additional data file. 11 Feb 2020 Serum Uric Acid a Depression Biomarker PONE-D-19-30310R2 Dear Dr. Meng, We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements. Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication. Shortly after the formal acceptance letter is sent, an invoice for payment will follow. To ensure an efficient production and billing process, please log into Editorial Manager at https://www.editorialmanager.com/pone/, click the "Update My Information" link at the top of the page, and update your user information. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org. If your institution or institutions have a press office, please notify them about your upcoming paper to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, you must inform our press team as soon as possible and no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. With kind regards, Kenji Hashimoto, PhD Section Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: 19 Feb 2020 PONE-D-19-30310R2 Serum Uric Acid a Depression Biomarker Dear Dr. Meng: I am pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org. For any other questions or concerns, please email plosone@plos.org. Thank you for submitting your work to PLOS ONE. With kind regards, PLOS ONE Editorial Office Staff on behalf of Prof. Kenji Hashimoto Section Editor PLOS ONE
  34 in total

1.  Association between serum uric acid level and components of the metabolic syndrome.

Authors:  Shi-Dou Lin; Dong-Hwa Tsai; Shang-Ren Hsu
Journal:  J Chin Med Assoc       Date:  2006-11       Impact factor: 2.743

2.  Serum uric acid levels in patients with Parkinson's disease: their relationship to treatment and disease duration.

Authors:  Elisabeth Andreadou; Chryssoula Nikolaou; Filippos Gournaras; Michael Rentzos; Fotini Boufidou; Anthoussa Tsoutsou; Christos Zournas; Vassilis Zissimopoulos; Demetrios Vassilopoulos
Journal:  Clin Neurol Neurosurg       Date:  2009-07-24       Impact factor: 1.876

3.  Serum uric acid and cardiovascular mortality the NHANES I epidemiologic follow-up study, 1971-1992. National Health and Nutrition Examination Survey.

Authors:  J Fang; M H Alderman
Journal:  JAMA       Date:  2000-05-10       Impact factor: 56.272

Review 4.  Depression's multiple comorbidities explained by (neuro)inflammatory and oxidative & nitrosative stress pathways.

Authors:  Michael Maes; Marta Kubera; Ewa Obuchowiczwa; Lisa Goehler; Joanna Brzeszcz
Journal:  Neuro Endocrinol Lett       Date:  2011       Impact factor: 0.765

5.  Serum uric acid in patients with Parkinson's disease and vascular parkinsonism: a cross-sectional study.

Authors:  Mengqiu Pan; Huimin Gao; Ling Long; Yunqi Xu; Mei Liu; Jing Zou; Aimin Wu; Xiaobo Wei; Xiaohong Chen; Beisha Tang; Qing Wang
Journal:  Neuroimmunomodulation       Date:  2012-11-14       Impact factor: 2.492

6.  Clinical correlation of alteration of endogenous antioxidant-uric acid level in major depressive disorder.

Authors:  Kiran Chaudhari; S Khanzode; S Khanzode; G Dakhale; A Saoji; S Sarode
Journal:  Indian J Clin Biochem       Date:  2010-02-10

7.  The relationship between uric acid levels and Huntington's disease progression.

Authors:  Peggy Auinger; Karl Kieburtz; Michael P McDermott
Journal:  Mov Disord       Date:  2010-01-30       Impact factor: 10.338

8.  Global burden of depressive disorders in the year 2000.

Authors:  T B Ustün; J L Ayuso-Mateos; S Chatterji; C Mathers; C J L Murray
Journal:  Br J Psychiatry       Date:  2004-05       Impact factor: 9.319

9.  Validation of the Edinburgh Postnatal Depression Scale against both DSM-5 and ICD-10 diagnostic criteria for depression.

Authors:  Johanne Smith-Nielsen; Stephen Matthey; Theis Lange; Mette Skovgaard Væver
Journal:  BMC Psychiatry       Date:  2018-12-20       Impact factor: 3.630

10.  A Double-edged Sword: Uric Acid and Neurological Disorders.

Authors:  Pu Fang; Xinyuan Li; Jin Jun Luo; Hong Wang; Xiao-Feng Yang
Journal:  Brain Disord Ther       Date:  2013-11-01
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  5 in total

1.  Serum uric acid is not associated with major depressive disorder in European and South American populations: a meta-analysis and two-sample bidirectional Mendelian Randomization study.

Authors:  Zefeng Chen; Shuang Liang; Yulan Bai; Jiali Lin; Mingli Li; Zengnan Mo; Sisi Xie; ShiShan Huang; Jianxiong Long
Journal:  Eur J Clin Nutr       Date:  2022-05-25       Impact factor: 4.016

2.  Depression, anxiety, and diabetes-related distress in type 2 diabetes in primary care in Greece: Different roles for glycemic control and self-care.

Authors:  Kyriakos Kintzoglanakis; Anna Gkousiou; Paraskevi Vonta; Agisilaos Sagmatopoulos; Panagiota Copanitsanou
Journal:  SAGE Open Med       Date:  2022-05-12

Review 3.  Why Does Hyperuricemia Not Necessarily Induce Gout?

Authors:  Wei-Zheng Zhang
Journal:  Biomolecules       Date:  2021-02-14

Review 4.  The Purinergic System as a Target for the Development of Treatments for Bipolar Disorder.

Authors:  Maria Carolina Bittencourt Gonçalves; Roberta Andrejew; Carolina Gubert
Journal:  CNS Drugs       Date:  2022-07-13       Impact factor: 6.497

Review 5.  Research progress of risk factors and early diagnostic biomarkers of gout-induced renal injury.

Authors:  Sheng Wang; Liyun Zhang; Dongsheng Hao; Lei Wang; Jiaxi Liu; Qing Niu; Liangyu Mi; Xinyue Peng; Jinfang Gao
Journal:  Front Immunol       Date:  2022-09-20       Impact factor: 8.786
  5 in total

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