European Journal of Cardiovascular Medicine

Most common mental illness affecting around 10 - 20% of general population is depression¹. In 2008, depression was ranked by World Health Organization, as the third cause of burden of disease worldwide and projected that it will rank first by 2030². Depression shares a major contribution to suicide deaths, with an incidence up to 800 per year worldwide ³. Depression is usually seen in early adulthood, with a mean age of onset of approximately 20-25 years⁴. Occurrence of depression is usually 2 fold higher in women than men at all age groups and several socio-demographic risk factors are involved in this trend ^5,6. Depression not only has a profound impact on patients themselves but also imposes a significant burden on families and society. It is therefore necessary to strengthen the research on the etiology, prevention and treatment of depression to effectively manage the condition. In the recent years, research has revolved around the metabolic markers and depression^7-11.

In human body, uric acid is the end product of purine metabolism.  It acts as a plasma free radical scavenger, accounting for more than half of the plasma antioxidant capacity. Therefore, it has neuroprotective effects. Additionally, UA stabilizes ascorbic acid, which is abundant in neurons. Thus, UA has particular significance in neurological diseases such as depression¹².

High-density lipoprotein cholesterol (HDL-C) is the most important lipoprotein in the human brain. It promotes removal of dietary cholesterol through the reverse cholesterol transport pathway and possesses anti-inflammatory and antioxidant properties, regulates neurodegeneration, and affects brain function¹³. To the interest of researchers, positive, negative, or non-existent correlation between HDL-C and depression has been seen^14-16. These contradictory findings inferred by the available literature, suggest a more complex dynamic regulatory mechanism, underlining the value of further study. Recently, the ratio of uric acid to high density lipoprotein cholesterol (UHR) has been seen as a new biomarker that reflects the inflammatory status and oxidative stress ^17-18.Based on this, it is hypothesized that the UHR ratio may be a new predictive biomarker marker for depression.

With this background, we investigate the association between UHR and depression risk among the participants, in order to provide guidance for future public health strategies and directions for preventing the occurrence and development of depression.

AIMS AND OBJECTIVES:

1. To study the association of serum uric acid with depression
2. To study the association of High density lipoproteins with depression
3. To assess the impact of uric acid to high density lipoprotein ratio (UHR) on depression.

The present case control study was carried out in department of Biochemistry, Vilasrao Deshmukh Government Medical College, Latur, India from march 2021 to 2023. The cases included 60 diagnosed patients of depression who presented to OPD in the Psychiatry department at Vilasrao Deshmukh Government Medical College, Latur.  Studyparticipants were in the age range of 20 -60 years and they were free from any medication for at least 2 weeks.  

Diagnosis of depression

The diagnosis of depression was done according to DSM-IV criteria.  Depressive symptoms were assessed using the 9-item Patient Health Questionnaire (PHQ-9). In the questionnaire, each item is scored from 0 (“not at all”) to 3 (“nearly every day”), with a total score ranging from 0 to 27. A PHQ-9 score of ≥ 10 was used to diagnose depression¹⁹.

The patients with prior clinical and/ or laboratory evidence sof hypo or hyper lipoprotenemia, alcohol dependence, or auto immune disease or somatic diseases (diabetes, renal or hepatic disorders) were excluded from the study. Pregnant or lactating women or those who were on an oestrogen therapy and contraceptives were also excluded from study. 

60 age and sex matched healthy controls who belonged to similar socio economic and geographical background as the patients group, were included in the study.  An ethical clearance was obtained from the institutional ethical committee. After obtaining written and informed consent from the subjects in the study and the control groups, 3ml blood was collected from each participants and the sera were separated.

Calculation of uric acid to High Density Lipoprotein Ratio (UHR): The serum levels of Uric acid and High Density Lipoproteins were estimated by using uricase peroxidase coupled method and HDL direct method respectively on Fully Automated Clinical Chemistry Analyzer, Transasia EM 360.  Ratio of uric acid to HDL –C (UHR)  (%) was calculated by dividing Uric acid (mg/dL) by HDL-C (mg/dL) and multiplying by 100%. Participants were divided into four groups (Q1–Q4) based on UHR quartiles, with Q1 as the control group.

Statistical analysis

In statistical analyses, Categorical variables were expressed as frequencies (percentages), while continuous variables were expressed as means (SE). Weighted linear regression and weighted chi-square tests were used to compare differences between baseline continuous and categorical variables. Student’s t-test was used for continuous variables, and the Rao Scott chi-square test was used for categorical variables. A multivariate logistic regression model was used to study the relationship between UHR and depression. For all these tests, a p< 0.05 was considered to reflect Statistical significance.

Results: proportion of females were high among the depressive cases with lower education levels, were more likely to be unmarried, lower serum HDL-C levels, higher triglyceride levels.

The present case-control study included 60 depressive patients and 60 age- and sex-matched healthy controls. The socio-demographic and anthropometric characteristics of the study population are summarized in Table 1. There were no significant differences in age, height, weight, sex distribution, marital status, religion, education level, dietary habits, or socioeconomic status between the cases and controls (all p > 0.05), ensuring comparability of groups.

Anthropometric and Socio-demographic Profiles

The mean age of depressive patients was 41.03 ± 10.26 years, while in the control group it was 40.23 ± 10.29 years (p = 0.67). Both groups had identical gender distribution, with 12 males and 48 females (p = 1.0). Other parameters like height and weight also showed no statistically significant differences (p = 0.15 and 0.76, respectively). Marital status, religion, educational attainment, dietary preferences, and socioeconomic background were statistically comparable across both groups (NS = Not Significant).

Table 1: Anthropometric and Socio-demographic Profiles of Healthy Controls and Depressive Cases

Table 2: Biochemical Parameters in Controls and Depressive Cases

Table 3: Association Between UHR and Depression

The present study observed lower levels of serum uric acid in Depressive cases (mean4.8±1.48) as compared to controls (Mean5.50±1.14) and the difference was statistically significant(p<0.001). The study also observed lower levels of serum HDL-C in Depressive cases (mean 50.76±12.23) as compared to controls (Mean56.27±16.23) with a statistically significant difference (p<0.001), as indicated in Table 2.

Relationship between UHR and depression:  In this study, it is observed that an increase in UHR was associated with an increased likelihood of depression (Table 3). In Model 1, without adjusting for any covariates, the odds ratio (OR) was 1.01 (95% CI, 1.00–1.02; P = 0.05). Model 2 adjusted for age, sex, (OR = 1.04; 95% CI, 1.03–1.05; P < 0.001). Model 3 further controlled for additional covariates, revealing a significant correlation (OR = 1.03; 95% CI, 1.02–1.04; P < 0.001). In the sensitivity analysis using UHR as a categorical variable (quartiles), individuals in the highest UHR category showed an increased association with depression compared to those with the lowest UHR. Therefore, elevated UHR levels may be a risk factor for depression.

In this case control study, we observed a unique correlation between the Uric acid to HDL-C ratio (UHR) in depression. In the fully adjusted model, Multivariate logistic regression analysis showed that, individuals with the highest UHR had increased probability of depression compared to those with the lowest UHR. It is demonstrated that, association between UHR and depression was consistent in the depressive cases and was not affected by covariates. This finding substantiates and amplify hypothesis of this study, emphasizing the complex involvement of UHR in depression, and provides valuable insights into the role of lipid metabolic processes in the development of depression. Hence, serum UHR levels have the promising role to serve as biomarkers for assessing depression risk, providing strong support for the diagnostic process. reduction in the UHR levels, by dietary adjustments or medications, may help to reduce the risk of depression in individuals with higher UHR levels.

Despite of the fact that, earlier studies have not explored the role of UHR in depression, the associations between UA, HDL-C, and depression have been widely considered. A study conducted by Lehto, S. M. et al, on 124 patients with depression evaluated levels of TC, HDL-C, LDL-C, and triglycerides. The study showed that, compared with healthy controls, long term depressed patients may have lower HDL-C values and higher atherosclerosis indices²⁰.

Maes, M. et al. studied 36 Major depressive patients, found changes in blood lipid components and their association with suicide, major depression, and immune-inflammatory responses. This study observed that lower Serum HDL-C levels are markers of severe depression and suicidal behaviour in depressed men²¹. Zhang, M et al.  found that, the risk of depression was significantly positively correlated with factors such as triglycerides and negatively correlated with HDL-C ²². These earlier studies, indirectly support our findings. Results of the various clinical trials, revealed significantly lower levels of uric acid in depression than the other types of mental disorders and healthy controls. Treatment with antidepressant for 5 weeks resulted in restoration of normal uric acid levels²³. To sum up, in this study the UHR, provides a new proof, that increases the understanding of the relationship between UHR and depression risk.

UHR is the measure of balance between the antioxidant property of Uric acid and the anti-inflammatory effect of HDL-C. In patients with depression, the increase of this ratio may mean higher levels of oxidative stress and inflammation in the body, which is consistent with the pathological mechanism of depression. This is intimately related with the two main components of UHR, that is UA and HDL-C.  UA, as an effective metabolic antioxidant, possesses antioxidant properties. As faar the close association between depression and oxidative stress is considered, it is the imbalance between ROS production and antioxidant defense mechanisms that can lead to cell damage and dysfunction²⁴ and hence, oxidative stress can be reduced by elevated UA levels. UA is neuroprotective in nature, as it reduces neuro inflammation and prevents neuronal apoptosis, and maintains integrity and function of nervous system²⁵. In addition, UA can regulate neurotransmitter systems, enhance dopamine release and receptor function, and modulate glutamate neurotransmission, which is related to the pathophysiology of depression²⁶. HDL –C, commonly called as good cholesterol, reduce levels of pro-inflammatory factors, thereby diminishing the inflammatory load on the nervous system through its interaction with vascular endothelial cells²⁷. paraoxonase-1, an antioxidant enzyme associated with HDL-C, acts as scavenger of free radicals and reduces the accumulation of reactive oxygen species within the body there by enhancing the anti-oxidant capacity of the nervous system²⁸.According  to “cholesterol-serotonin” model, a decrease in serum cholesterol levels may reduce cell membrane fluidity,  thereby causing prevention of  full exposure of serotonin receptors on the cell membrane and  further reduces the  intracellular serotonin and increases depression risk. The decreased cholesterol causes increased serotonin reuptake efficiency and reduces available serotonin and leads to depression²⁹.

As a biomarker reflecting the levels of inflammation and oxidative stress, UHR holds significant potential for contributing to the clinical diagnosis, treatment monitoring, and prognostic assessment of depression.

The present study concludes that, UHR, as a new biomarker, indicates higher levels of oxidative stress and inflammatory burden, the factors which ultimately associated with the occurrence of depression. The impact of UHR levels on depression risk is complex. Further prospective studies with larger sample size are needed to exactly explain the causal relationship between elevated serum UHR levels and depression risk.

Conflict of interest: Nil

1. Lim, G.Y.; Tam, W.W.; Lu, Y.; Ho, C.S.; Zhang, M.W.; Ho, R. Prevalence of Depression in the Community from 30 Countries between 1994 and 2014. Sci. Rep. 2018, 8, 2861.
2. World Health Organization. The Global Burden of Disease: 2004 Update; World Health Organization: Geneva, Switzerland, 2008
3. World Health Organization. Depression and Other Common Mental Disorders: Global Health Estimates; World Health Organization: Geneva, Switzerland, 2017.
4. Malhi, G.S.; Mann, J.J. Depression. Lancet 2018, 392, 2299–2312.
5. Kessler, R.C.; Bromet, E.J. The Epidemiology of Depression Across Cultures. Annu. Rev. Public Health 2013, 34, 119–138.
6. Kuehner, C. Why is depression more common among women than among men? Lancet Psychiatry 2017, 4, 146–158.
7. de la Torre-Luque, A., Ayuso-Mateos, J. L., Sanchez-Carro, Y., de la Fuente, J. & Lopez-Garcia, P. Inflammatory and metabolic disturbances are associated with more severe trajectories of late-life depression. Psychoneuroendocrinology 110, 104443 (2019).
8. Wigner, P., Czarny, P., Galecki, P., Su, K. P. &Sliwinski, T. The molecular aspects of oxidative &nitrosative stress and the tryptophan catabolites pathway (TRYCATs) as potential causes of depression. Psychiatry Res. 262, 566–574 .(2018).
9. Jiang, Y. et al. Dysregulations of amino acid metabolism and lipid metabolism in urine of children and adolescents with major depressive disorder: a case-control study. Psychopharmacology 241, 1691–1703 (2024).
10. Yang, S., Li, Y., Tang, Q., Zhang, Y. & Shao, T. Glucose metabolic abnormality: a crosstalk between depression and Alzheimer’s disease. Curr. Neuropharmacol. (2024).
11. Ho, C. S. H., Tay, G. W. N., Wee, H. N. &Ching, J. The utility of amino acid metabolites in the diagnosis of major depressive disorder and correlations with Depression Severity. Int. J. Mol. Sci. 24, 10058. (2023).
12. Mangas, A. et al. Overexpression of kynurenic acid in stroke: an endogenous neuroprotector? Ann. Anat. 211, 33–38. (2017).
13. Crudele, L. et al. Low HDL-cholesterol levels predict hepatocellular carcinoma development in individuals with liver fibrosis. JHEP Reports: Innov. Hepatol. 5, 100627. (2023).
14. Penninx, B. W., Milaneschi, Y., Lamers, F. &Vogelzangs, N. Understanding the somatic consequences of depression: biological mechanisms and the role of depression symptom profile. BMC Med. 11, 129. (2013).
15. Moreira, F. P. et al. Metabolic syndrome, depression and anhedonia among young adults. Psychiatry Res. 271, 306–310. (2019).
16. De Wit, A. E. et al. Associations between testosterone and metabolic syndrome in depressed and non-depressed older men and women. Int. J. Geriatr. Psychiatry 34, 463–471. (2019).
17. KolahiAhari, R. et al. Serum uric acid to high-density lipoprotein ratio as a novel indicator of inflammation is correlated with the presence and severity of metabolic syndrome: a large-scale study. Endocrinol. Diabetes Metabol. 6, e446. (2023).
18. Gao, H. et al. A large-scale study on uric acid-related biomarkers in patients with bipolar disorder. Psychiatry Res. 339, 116089. (2024).
19. Kroenke, K., Spitzer, R. L. & Williams, J. B. The PHQ-9: validity of a brief depression severity measure. J. Gen. Intern. Med. 16, 606–613. (2001).
20. Lehto, S. M. et al. Low HDL cholesterol associates with major depression in a sample with a 7-year history of depressive symptoms. Prog. Neuro-psychopharmacol. Biol. Psychiatry 32, 1557–1561. (2008).
21. Maes, M. et al. Lower serum high-density lipoprotein cholesterol (HDL-C) in major depression and in depressed men with serious suicidal attempts: relationship with immune-inflammatory markers. Acta Psychiatry Scand. 95, 212–221. (1997).
22. Zhang, M., Chen, J., Yin, Z., Wang, L. & Peng, L. The association between depression and metabolic syndrome and its components: a bidirectional two-sample mendelian randomization study. Transl. Psychiatry 11, 633. (2021).
23. Liu, Y., Zhang, X., Wang, P., Yang, M. & Li, N. Comparison of clinical features, serum lipid, and uric acid levels in patients with unipolar depression and bipolar depression. Psychiatry Clin. Psychopharmacol. 32, 313–319. (2022).
24. Bhatt, S., Nagappa, A. N. & Patil, C. R. Role of oxidative stress in depression. Drug Discov. Today 25, 1270–1276. (2020).
25. Myint, A. M. et al. Kynurenine pathway in major depression: evidence of impaired neuroprotection. J. Affect. Disord. 98, 143–151. (2007)
26. Salimi, A., Mamkhezri, H. &Hallaj, R. Simultaneous determination of ascorbic acid, uric acid and neurotransmitters with a carbon ceramic electrode prepared by sol-gel technique. Talanta 70, 823–832. (2006).
27. Nazir, S. et al. Interaction between high-density lipoproteins and inflammation: function matters more than concentration! Adv. Drug Deliv. Rev. 159, 94–119. (2020).
28. Morris, G. et al. The role of high-density lipoprotein cholesterol, apolipoprotein A and paraoxonase-1 in the pathophysiology of neuroprogressive disorders. Neurosci. Biobehav. Rev. 125, 244–263. (2021).
29. Andrews, P. W. et al. All the brain’s a stage for serotonin: the forgotten story of serotonin diffusion across cell membranes. Proc. Biol. Sci. 289, 20221565. (2022).
30.