Association between lipid ratio and depression: a cross-sectional study

Via Peters

In this study, we examined the relationship between depression and three lipid ratios, namely TC/HDL-C, LDL-C/HDL-C, and TG/HDL-C. The results showed that there is an association between TG/HDL-C and depression in men. However, TC/HDL-C and LDL-C/HDL-C were not associated with depression in both men and women.

Previous studies have mainly focused on the relationship between the abovementioned lipid ratios and cardiovascular disease and insulin resistance13,14,15,16. However, no previous study has been conducted to analyze the association between these ratios and depression. Some studies have demonstrated that the TC/HDL-C ratio is an important marker of cardiovascular risk and is mainly associated with insulin resistance13,14,16,17. As shown by the Framingham risk score, the risk of coronary artery disease increases with increase in the TG/HDL-C ratio12. In addition, a high TG/HDL-C ratio predicts the presence of small and dense LDL particles, and is useful for diagnosing the onset of insulin resistance and metabolic syndrome18.

Previous studies have shown that low TC and LDL-C levels are correlated with the onset of depression15,16,19,20. There are some plausible explanations for this relationship. First, depression reduces a patient’s appetite, leading to a low serum TC level19. Second, cytokine activation, which interferes with cholesterol synthesis, occurs in depression21. Third, low cholesterol level can reduce the availability of serotonin, making the patient more susceptible to depression16.

A study conducted on 8390 people using data from the National Health Survey of the United States demonstrated an association between depression and cholesterol level. Depression was diagnosed using the PHQ-9, and LDL-C levels were divided into three groups: < 169 mg/dL, 169–221 mg/dL, and ≥ 222 mg/dL. The results showed that compared to the moderate group (169–221 mg/dL), the OR for depression was 5.13 (1.74–15.09) in the low group (< 169 mg/dL) and 2.28 (1.07–4.86) in the high group (222 mg/dL or higher), which showed a U-shaped relationship. However, LDL-C and HDL-C were not associated with moderate depression15. Although the LDL-C level is known to be associated with depression, our study identified a relationship between cholesterol ratio and depression, revealing the importance of evaluating lipid ratio.

Low cholesterol levels are associated with mental health indicators. The association between low cholesterol level and depression has been consistently proven in laboratory studies. In addition, less favorable or depressive behaviors were observed in studies of animals with low cholesterol levels22,23. In a previous report, patients who used cholesterol-lowering drugs long-term showed signs of depression20. These findings can be explained by the significant correlation between plasma serotonin and low cholesterol concentration, which has been previously reported2,24.

Similar to the present study, some previous studies showed that depression is associated with high TG and low HDL-C levels25,26. A recent meta-analysis performed to investigate whether lipid parameters differed between healthy individuals and patients with first-episode major depressive disorder revealed that elevated TG and decreased HDL-C levels are associated with first-episode major depressive disorder25. Although the TG and HDL-C levels are known to be associated with depression, our study identified a relationship between TG/HDL-C ratio and depression, revealing that evaluation of lipid ratio is crucial.

The serum lipid levels of people with depression and suicidal ideation have been analyzed in a previous study using KNHANES data, the results of which showed a significant association of high HDL-C and TG levels with depression26. However, unlike the present study, it was conducted using KNHANES data from 2014, and depression was diagnosed as a PHQ-9 score ≥ 5.

The potential mediators of depression in lipids or lipoproteins and their association with the heterogeneity of symptoms have been investigated in a previous study27. The results indicated that melancholic features are independently associated with low HDL-C level, whereas atypical depression is independently associated with high TC and LDL-C levels27.

The results of the present study are consistent with the findings of previous studies that suggest that depression is associated with metabolic syndrome. Research on the relationship between metabolic syndrome and depression has been actively conducted in recent years6,28,29. Several possible mechanisms may be behind this correlation between metabolic syndrome and depression. Individuals with depression are more likely to engage in unhealthy behaviors, such as smoking, drinking alcohol, unhealthy diet and lifestyle, and non-compliance with medical treatment, than those who are not29. In addition, depression causes dysregulation of the hypothalamic–pituitary–adrenal axis, which may explain its association with metabolic syndrome30. There is a study that analyzed whether CRP and TG were related to suicide attempts in patients with major depressive disorder. The results of the study showed that CRP was significantly higher in suicide attempters than in depressed patients who did not attempt suicide and in healthy controls. TG levels were significantly higher in depressed patients compared to healthy controls31.

The presence of depression was analyzed in this study using PHQ-9 scores. The usefulness of the PHQ-9 score as a diagnostic criterion for depression has already been verified in Korea and in other countries7,8,9. However, the score used as a diagnostic criterion varies from study to study. In the present study, a PHQ-9 score  10 was diagnosed as depression. In the study by Kroenke et al.19, a cutoff of 9 points had a high sensitivity of 95% and a specificity of 84%. However, 10 points, which is simple and easy to remember or apply in actual clinical settings, has been suggested as the optimal cutoff point32.

A review journal reports that the association between depression and lipid profile leads to several conclusions33. That is, some studies reported that the lower the cholesterol level, the more adversely affected depression, and other studies reported no relationship. Although our results cannot hypothesize an association between lipid profile and depression, it can be hypothesized that at least TG/HDL-C is associated with depression mediated by weight gain or poor lifestyle.

The present study is meaningful because it is the first to analyze the association between lipid ratios and depression in a large population. The results of this study indicate that TC/HDL-C and LDL-C/HDL-C are not associated with depression. However, this finding may have been influenced by the sample size, design, and participants of this study. Therefore, future large-scale prospective clinical studies are needed to verify this conclusion.

This study has some limitations. First, we used data from a study in which depression and lipid levels were measured only once. Depression and cholesterol levels are likely to fluctuate over time; thus, failure to account for these fluctuations may have clouded the observed association. Second, the data used in the study are from large-scale government surveys, and there were several limitations in statistical analysis. Degree and characteristics of depression, presence of suicidal ideation/attempts were not investigated. Additionally, administration of psychotropic medications or cognitive therapy were not investigated. Third, as this was a cross-sectional study, it was difficult to ascertain the relationship between low cholesterol level and depression.

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