|Year : 2019 | Volume
| Issue : 1 | Page : 35-40
Serum uric acid level and its association with severity of manic and depressive symptoms
Hani H Dessoki, Maha Emadeldin, Ahmed A Ezzat, Hisham Salah, Sarah M Hakim
Department of Psychiatry, Faculty of Medicine, Beni-Suef University, Beni-Suef, Egypt
|Date of Submission||22-Jan-2019|
|Date of Acceptance||04-Feb-2018|
|Date of Web Publication||9-May-2019|
Department of Psychiatry, Faculty of Medicine, Beni-Suef University, 12572 Al-Remaya, Giza
Source of Support: None, Conflict of Interest: None
Background Prior reports pointed out that individuals having bipolar disorder (during manic episodes) and those with major depressive episode might have changes in their serum uric acid (SUA) levels. The aim of the study was to investigate SUA levels in patients with bipolar I (current manic episode) and major depressive disorders (MDDs) compared with healthy controls.
Participants and methods A cross-sectional case–control study with consecutive sampling of 90 participants was conducted. Psychiatric assessment for all participants was performed using the Structured Clinical Interview for DSM IV-TR Axis I Disorders, Arabic version (SCID I). Young mania rating scale and Hamilton depression rating scale were introduced to patients with bipolar disorder I and MDD, respectively, to assess the illness severity. Blood samples were obtained through venipuncture after overnight fasting from 10 to 12 h.
Results SUA showed significant higher levels in bipolar disorder group (mean=5.95±0.55) than MDD group (mean=3.36±0.66) and controls (mean=4.54±0.65, P=0.00). On the contrary, SUA revealed a statistically significant lower level in MDD group than controls (P=0.00). There is no significant correlation between SUA levels and severity of current manic and depressive symptoms (P=0.44 and 0.80, respectively).
Conclusion SUA levels were significantly higher in patients with manic symptoms than in patients with depressive symptoms and controls. There is no significant association of SUA and severity of manic or depressive symptoms.
Keywords: bipolar, depression, severity, uric acid
|How to cite this article:|
Dessoki HH, Emadeldin M, Ezzat AA, Salah H, Hakim SM. Serum uric acid level and its association with severity of manic and depressive symptoms. Egypt J Psychiatr 2019;40:35-40
|How to cite this URL:|
Dessoki HH, Emadeldin M, Ezzat AA, Salah H, Hakim SM. Serum uric acid level and its association with severity of manic and depressive symptoms. Egypt J Psychiatr [serial online] 2019 [cited 2019 Dec 7];40:35-40. Available from: http://new.ejpsy.eg.net/text.asp?2019/40/1/35/257847
| Introduction|| |
Mood disorders are among the most distressing mental health problems with high rate of disability. So, recognizing reliable biomarkers could help in early detection and management (Chaudhari et al., 2010). Dysfunction of purinergic system could be a promising indicator in understanding the pathophysiology of mood disorders as suggested by genetic and clinical research (Machado-Vieira et al., 2008). Several studies support the presence of purinergic dysfunction in patients with mood disorders (De Berardis et al., 2008; Kesebir et al., 2013; Muti et al., 2015; Bartoli et al., 2016).
Purines play an essential role in neurotransmission and might be involved in the pathophysiology of several mental disorders (Burnstock, 2007; Abbracchio et al., 2009). It was identified that purinergic receptors interact with adenosine and ATP during neurotransmission (Krügel et al., 2004). It has been theorized that the reduced action of adenosine, especially on A1 receptors, might play a role in dysfunction of neurotransmitter pathways involved in bipolar disorder (BD) and related manic symptoms (Machado-Vieira et al., 2002).
On the contrary, lower SUA level in major depressive disorder (MDD) could be understood as reflecting dysfunction of the purine cycle (Ortiz et al., 2015). Another explanation to the lower SUA levels may be owing to the utilization of SUA by radical interaction and damaged tissue (Maes et al., 2011), as depression was reported to be associated with oxidative stress, as measured by 8-hydroxy-2′-deoxyguanosine and F2-isoprostanes (Black et al., 2015). Moreover, Ali-Sisto et al. (2016) suggested that hyperactivity of the purine degradation cycle in depressed patients may be related to an attempt to provide sufficient uric acid to counteract increased oxidative stress. Consequently, this altered purine cycle leads to decreased SUA level.
The aims of this study are (a) to compare the levels of serum uric acid (SUA) in patients with recent manic episode, those with recent depressive episode, and healthy controls and (b) to assess the relation between SUA level and severity of manic and depressive symptoms.
| Participants and methods|| |
This is a cross-sectional case–control study conducted from July 2017 to January 2018 through consecutive sampling of 90 participants [30 patients with BD I (recent manic episode), 30 patients with MDD and 30 healthy controls]. This is a cross-sectional case/control study conducted from July 2017 to January 2018. Ninety subjects participated in this study through consecutive sampling. They were divided into three groups [30 patients with BDI with recent manic episode, 30 patients with MDD and 30 healthy controls. Patients were recruited from Outpatient Clinic and Inpatient Department of the Psychiatry and Addiction Hospital, Kasr Al-Ainy, Cairo University. The control group included healthy volunteers who matched with the patient group regarding age, sex, and socioeconomic status. All participants who participated were of both sexes with age were from 18 to 55 years and with clinically average intelligence.
Individuals with a history suggestive of metabolic syndrome were excluded (measurement of waist circumference ≥102 cm in men or ≥88 cm in women and systolic blood pressure ≥130 mmHg or diastolic blood pressure ≥85 mmHg). Moreover, individuals with organic brain diseases, other axis I diagnoses, chronic medical illness, diagnosed with gout or received allopurinol as treatment for gout, or taking other drugs that could alter SUA levels were excluded from the study. Severely agitated patients and pregnant or lactating females were also excluded.
Patients were diagnosed by a senior psychiatrist according to Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revised (DSM IV-TR) criteria, and those who fulfilled the inclusion criteria were directed to the research. The diagnosis of patients with BD and MDD were confirmed using the Arabic version of Structured Clinical Interview for DSM IV-TR Axis I Disorders (SCID I) (El Missiry et al., 2003). The Young mania rating scale was used to assess the severity of mania (Young et al., 1978), whereas the severity of MDD was assessed by Hamilton depression rating scale (HAMD) (Hamilton, 1960).
A total of 54 patients with BD were invited to join the study, and 24 of them dropped out, whereas 47 patients with MDD were invited to join the study, and 17 dropped out. The dropout reasons were failure to obtain an informed written consent, not meeting the exclusion criteria of metabolic syndrome parameters, and not showing up fasting on the second appointment to obtain the required samples.
An informed written consent was taken from patients and healthy controls after discussing with them the aim of the study and procedure. This work has received the approval of the Ethics Research Committee, Faculty of Medicine, Beni-Suef University.
Serum uric acid measurement
Morning venous blood samples (5 ml) were withdrawn from all participants after an overnight fast (10–12 h). Aliquots of serum were obtained in vacutainer tubes containing EDTA. Samples were centrifuged at 3000 g for 15 min and stored at 80°C until assay. Samples were tested for SUA and serum triglycerides levels using automated chemistry. The normal reference level of uric acid is 1.5–6.0 mg/dl in women and 2.5–7.0 mg/dl in men. Levels above the normal reference level were excluded from the study. Normal triglycerides levels is less than 150 mg/dl. Levels above this range were also excluded from the study.
The collected data were tabulated, coded, and analyzed using SPSS for Windows, version 20 (SPSS Inc., Chicago, Illinois, USA). Continuous variables were presented as mean values±SD and categorical variables were presented as percentages. For qualitative data, comparisons were done using χ2-test. For quantitative data, t-test and analysis of variance were used, and P value less than 0.05 was considered statistically significant (IBM, 2011).
| Results|| |
Demographics and clinical data
The mean age of patients with BD I was 30.96±8.06 years, whereas for patients with MDD was 31.60±7.78 years, and it was 32.10±7.55 years for controls. Among patients with BD I, 53.3% were males and 46.7% were females, whereas among patients with MDD, 40.0% were males and 60.0% were females, and for controls, males constituted 53.3% of the group and 46.7% were females. Of all participants, 22.2% were illiterate, 52.2% were of middle education, and 25.6% were of higher education; moreover, 50% of all participants were unemployed and not married (see [Table 1]).
Among patients with BD I, 53.3% had no family history of psychiatric disorders compared with 70% for patients with MDD. Regarding duration of the current mood episode, patients with MDD showed a statistically significant longer duration of illness since the start of the current episode. The mean duration of the current episode in patients with MDD was 5.25±3.87 weeks, whereas in the BD group, the mean duration of the current episode was 3.45±2.41 weeks (see [Table 1]).
Serum uric acid
SUA was significantly higher in BD group (mean=5.95±0.55) than MDD group (mean=3.36±0.66) and controls (mean=4.54±0.65). On the contrary, SUA level was significantly lower in MDD group compared with controls (P=0.00) (see [Table 2]).
Correlation of serum uric acid
As shown in [Table 3], SUA level did not show any significant association with severity of manic symptoms nor depressive symptoms (P=0.44 and 0.80, respectively). Moreover, there was no significant correlation between SUA level and duration of illness in both groups (see [Table 4]).
|Table 3 Severity of the current mood episode in relation to serum uric acid levels|
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|Table 4 Correlation of serum uric acid levels and duration of the episode|
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| Discussion|| |
The present study was aimed at assessment of SUA in manic and depressed patients to allow the evaluation of this biomarker in patients with bipolar disorder and MDD. Moreover, it aimed at understanding the relation between SUA levels and the severity of mood symptoms.
This study indicated that there was a statistically significant difference between BD group (current manic episode), MDD group, and controls in terms of SUA levels (see [Table 2]).
It was found that cases within the BD group had a mean SUA level higher than control and patients with MDD. These results were consistent with other studies that investigated the presence of a purinergic dysfunction in patients with mood disorders (De Berardis et al., 2008; Kesebir et al., 2013; Muti et al., 2015; Bartoli et al., 2016).
This could be related to the fact that uric acid was found to be associated with externalized traits of temperament, such as disinhibition (Lorenzi et al., 2010; Ortiz et al., 2015), as well as impulsiveness and excitement seeking (Sutin et al., 2014).
An increased risk of developing gout among patients with BD has been described. Moreover, allopurinol, a xanthine oxidase inhibitor, is one of the most widely used hypouricemic agents, which showed antimanic efficacy as an add-on therapy in treatment-resistant mania, supporting the relationship between the emergence of manic symptoms and an increase of uric acid levels (Akhondzadeh et al., 2006; Machado-Vieira et al., 2011; Jahangard et al., 2014; Bartoli et al., 2017).
Machado-Vieira et al. (2002) suggested that high SUA levels in patients with manic disorder could be the outcome of the increased purinergic turnover, which would result in less adenosinergic transmission. On the contrary, other research studies claimed that increase in uric acid levels in BD could be owing to elevated rates of metabolic disorder in BD, instead of dysfunction in purinergic system (Bartoli et al., 2016). However, in this study, participants with metabolic syndrome were excluded to avoid the effect of metabolic disorders on purinergic system.
In this study, patients with MDD had lower SUA levels compared with patients with manic bipolar disorder and healthy controls. This was consistent with the findings of several studies (Chaudhari et al., 2010; Wen et al., 2012; Ali-Sisto et al., 2016; Soliman and Mahdy, 2018).
On the contrary, another study showed an increase in SUA in patient with MDD as compared with controls (Ran and Huan, 2015).
Regarding the severity of symptoms, this study revealed no significant relation between the severity of the disorder and SUA level in both patient groups (see [Table 3]). These findings were consistent with Soliman and Mahdy (2018) who found no significant correlation between severity of depressive symptoms and SUA level, although the lowest SUA was for patients with very severe depression. Moreover, Wen et al. (2012) found no significant difference between SUA level in severe depression (HAMD >35) and less severe depression (HAMD <35). In addition, Ali-Sisto et al. (2016) found no significant relation between severity of depression (using Beck depression inventory) and purine metabolites. Keshavarz et al. (2016) revealed no correlation between SUA levels and severity of mood disorders in both patients with manic disorder and those with depression.
On the contrary to our results, elevated SUA levels were positively correlated with severity of symptoms and with the improvement of manic symptoms (Machado-Vieira et al., 2008). Moreover, Muti et al. (2015) found the same findings when Clinical Global Impression Bipolar version Scale (CGI-BP) score was used to assess the severity of the disorder.
Using different tools in assessing the severity of symptoms in BD could be partially responsible for the contradictions of these findings. Our results could be partially explained by the fact that Young mania rating scale does not address at all symptoms like psychosis, impulsivity, high-risk behavior, or suicidal behavior (Prisciandaro and Tolliver, 2016).
Regarding depression, in contrary to our findings, Chaudhari et al. (2010) found an inverse relation between uric acid levels and HAMD scores at the time of diagnosis. In addition, De Berardis et al. (2008) found elevated SUA levels were positively correlated with the improvement depressive symptoms. Moreover, one study found that higher levels of SUA were associated with lower risk of hospitalization with depression and antidepressant medication use (Wium et al., 2017). Moreover, some studies found increased SUA levels after treatment with antidepressant drugs (Chaudhari et al., 2010; Wen et al., 2012; Soliman and Mahdy, 2018). This is supported by other study which stated that mental distress and suicidal tendency were related to lower uric acid serum levels (Bartoli et al., 2018).
When analyzing the relation between SUA level and duration of the current episode, results showed no significant correlation ([Table 4]). This could be in line with Wen et al. (2012), who studied the effect of duration of the illness on SUA level and revealed no difference between patients with longer duration of depression (>60 months) and shorter duration of depression (<60 months). Moreover, in a recent study by Black et al. (2018), using the data from the Netherlands Study of Depression and Anxiety, it was reported that longer duration of depressive symptoms was significantly related to lesser level of uric acid.
The use of medications could potentially be a limitation as mood stabilizers have proved to alter SUA levels through adenosinergic mechanisms (Albert et al., 2015). However, other studies such as by Salvadore et al. (2010) found elevated SUA level in drug-naive patients with bipolar disorder.
Further studies with a large randomized sample would help to give more precise data representing the study group. Confounders other than the parameters of the metabolic syndrome could be controlled well, such as diet, caffeine intake, and smoking. Selection of drug-naive patients may help to eliminate the effect of psychotropic medication on SUA level. This study investigate the SUA in the acute episode; however, follow-up study may be needed to investigate the level of SUA in different stages of illness.
| Conclusion|| |
To conclude, the results of this study added another evidence of the contribution of uric acid in the pathogenesis of mood disorders. It suggests the possibility of using SUA level as a biomarker for mania and depression.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Abbracchio MP, Burnstock G, Verkhratsky A, Zimmermann H (2009). Purinergicsignalling in the nervous system: an overview. Trends Neurosci 32:19–29.
Akhondzadeh S, Milajerdi MR, Amini H, Tehrani-Doost M (2006). Allopurinol as an adjunct to lithium and haloperidol for treatment of patients with acute mania: a double-blind, randomized, placebo-controlled trial. Bipolar Disord 8:485–489.
Albert U, De Cori D, Aguglia A, Barbaro F, Bogetto F, Maina G (2015). Increased uric acid levels in bipolar disorder subjects during different phases of illness. J Affect Disord 173:170–175.
Ali-Sisto T, Tolmunen T, Toffol E, Viinamäki H, Mäntyselkä P, Valkonen-Korhonen M, Lehto SM (2016). Purine metabolism is dysregulated in patients with major depressive disorder. Psychoneuroendocrinology 70:25–32.
Bartoli F, Crocamo C, Gennaro GM, Castagna G, Trotta G, Clerici M, Carrà G (2016). Exploring the association between bipolar disorder and uric acid: a mediation analysis. J Psychosom Res 84:56–59.
Bartoli F, Crocamo C, Clerici M, Carrà G (2017). Allopurinol as add-on treatment for mania symptoms in bipolar disorder: systematic review and meta-analysis of randomised controlled trials. Br J Psychiatry 210:10–15.
Bartoli F, Crocamo C, Gennaro GM, Castagna G, Trotta G, Bavaa M et al.
(2018). Testing the association of serum uric acid levels with behavioral and clinical characteristics in subjects with major affective disorders: a cross-sectional study. Psychiatry Res 269:118–123.
Black CN, Bot M, Scheffer PG, Cuijpers P, Penninx BW (2015). Is depression associated with increased oxidative stress? A systematic review and meta-analysis. Psychoneuroendocrinology 51:164–175.
Black CN, Bot M, Scheffer PG, Snieder H, Penninx BW (2018). Uric acid in major depressive and anxiety disorders. J Affect Disord 225:684–690.
Burnstock G (2007). Purine and pyrimidine receptors. Cell Mol Life Sci 64:1471–1483.
Chaudhari K, Khanzode S, Dakhale G, Saoji A, Sarode S (2010). Clinical correlation of alteration of endogenous antioxidant-uric acid level in major depressive disorder. Indian J Clin Biochem 25:77–81.
De Berardis D, Conti CM, Campanella D, Carano A, Di Giuseppe B, Valchera A et al.
(2008). Evaluation of plasma antioxidant levels during different phases of illness in adult patients with bipolar disorder. J Biol Regul Homeost Agents 22:195.
El Missiry A, Sorour A, Sadek A, Fahy TA, Mawgoud M, Asaad T (2003). Homicide and psychiatric illness: an Egyptian study [MD thesis]. Cairo: Faculty of Medicine, Ain Shams University.
Hamilton M (1960). A rating scale for depression. J Neurol Neurosurg Psychiatry 23:56.
IBM (2011) Statistical Package for Social Sciences (SPSS) Statistics for Windows, Released, Version 20.0. Armonk, NY: IBM Corp.
Jahangard L, Soroush S, Haghighi M, Ghaleiha A, Bajoghli H, Holsboer-Trachsler E, Brand S (2014). In a double-blind, randomized and placebo-controlled trial, adjuvant allopurinol improved symptoms of mania in in-patients suffering from bipolar disorder. Eur Neuropsychopharmacol 24:1210–1221.
Kesebir S, Süner O, Yaylaci ET, Bayrak A, Turan C (2013). Increased uric acid levels in bipolar disorder: is it trait or state? J Biol Regul Homeost Agents 27:981–988.
Keshavarz M, Khosravizadegan F, Bibak A (2016). Serum uric acid levels in different phases of acute severe manic and depressed patients. Arch Neurosci 3:2.
Krügel U, Spies O, Regenthal R, Illes P, Kittner H (2004). P2 receptors are involved in the mediation of motivation-related behavior. Purinergic Signal 1:21–29.
Lorenzi TM, Borba DL, Dutra G, Lara DR (2010). Association of serum uric acid levels with emotional and affective temperaments. J Affect Disord 121:161–164.
Machado-Vieira R, Lara DR, Souza DO, Kapczinski F (2002). Purinergic dysfunction in mania: an integrative model. Med Hypotheses 58:297–304.
Machado-Vieira R, Soares JC, Lara DR, Luckenbaugh DA, Busnello JV, Marca G, Kapczinski F (2008). A double-blind, randomized, placebo-controlled 4-week study on the efficacy and safety of the purinergic agents allopurinol and dipyridamole adjunctive to lithium in acute bipolar mania. J Clin Psychiatry 69:1237–1245.
Machado-Vieira R, Henter I, Baumann J, Latov D, Wheeler-Castillo C, Zarate CA (2011). Novel therapeutic approaches for treating bipolar disorder Bipolar Psychopharmacotherapy: Caring for the Patient. 2nd ed. Jon Wiley & Sons, Ltd.. 423–445. ISBN:978-0-470-74721-6
Maes M, Galecki P, Chang YS, Berk M (2011). A review on the oxidative and nitrosative stress (O&NS) pathways in major depression and their possible contribution to the (neuro) degenerative processes in that illness. Prog Neuropsychopharmacol Biol Psychiatry 35:676–692.
Muti M, Del Grande C, Musetti L, Marazziti D, Turri M, Cirronis M, Corsini GU (2015). Serum uric acid levels and different phases of illness in bipolar I patients treated with lithium. Psychiatry Res 225:604–608.
Ortiz R, Ulrich H, Zarate CA Jr, Machado-Vieira R (2015). Purinergic system dysfunction in mood disorders: a key target for developing improved therapeutics. Prog Neuropsychopharmacol Biol Psychiatry 57: 117–131.
Prisciandaro JJ, Tolliver BK (2016). An item response theory evaluation of the Young mania rating scale and the Montgomery-Asberg depression rating scale in the systematic treatment enhancement program for bipolar disorder (STEP-BD). J Affect Disord 205:73–80.
Ran T, Huan L (2015). High serum uric acid level in adolescent depressive patients. J Affect Disord 174:464–466.
Salvadore G, Viale CI, Luckenbaugh DA, Zanatto VC, Portela LV, Souza DO, Machado-Vieira R (2010). Increased uric acid levels in drug-naïve subjects with bipolar disorder during a first manic episode. Prog Neuropsychopharmacol Biol Psychiatry 34:819–821.
Soliman ES, Mahdy RS (2018). Serum uric acid level in drug-naïve depressed patients. Egypt J Psychiatry 39:78–82.
Sutin AR, Cutler RG, Camandola S, Uda M, Feldman NH, Cucca F, Terracciano A (2014). Impulsivity is associated with uric acid: evidence from humans and mice. Biol Psychiatry 75: 31–37.
Wen S, Cheng M, Wang H, Yue J, Wang H, Li G et al.
(2012). Serum uric acid levels and the clinical characteristics of depression. Clin Biochem 45:49–53.
Wium AMK, Kobylecki CJ, Afzal S, Nordestgaard BG (2017). Association between the antioxidant uric acid and depression and antidepressant medication use in 96 989 individuals. Acta Psychiatr Scand 136:424–433.
Young RC, Biggs JT, Ziegler VE, Meyer DA (1978). A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry 133:429–435.
[Table 1], [Table 2], [Table 3], [Table 4]