Serum lipid level as a biomarker in depressive disorder: A cross-sectional case control study

INTRODUCTION

Depression is a widespread mental health disorder affecting a diverse range of people globally. According to estimates, it impacts roughly 350 million individuals worldwide.^[1] A leading cause of disability, particularly among young adults (aged 25–49), depression ranks sixth in disability-adjusted life years as of 2019.^[2] The severity of depression varies considerably, ranging from mild to severe, and is determined by the intensity of symptoms and their impact on daily functioning.^[3-5] Characterized by a combination of emotional, cognitive, and physical symptoms, depression manifests differently in each person.^[3] Mounting research delves into the connections between depression and physiological factors, with a particular focus on abnormalities in lipid profiles.^[6] Several studies suggest that individuals with depression might exhibit disruptions in their lipid profile levels.^[7-9] For instance, Glueck et al. observed significantly lower levels of total cholesterol (TC), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) in patients diagnosed with affective disorders encompassing depression.^[10] Similarly, Olusi and Fido reported lower serum TC levels in patients with major depressive disorder (MDD) compared to a healthy control group. These findings suggest a potential association between low serum TC and depression across various age groups and genders. Anhedonia, a core symptom of depression, has also been linked to lipid profile abnormalities.^[11] Moreira et al. reported elevated LDL levels in individuals with unipolar depression and anhedonia.^[4] However, Su et al. found contrasting results, with depressed patients experiencing anhedonia having lower LDL levels compared to those without anhedonia. These conflicting findings highlight the intricate nature of the relationship between anhedonia, lipid profiles, and depressive symptoms, underscoring the need for further research to gain a comprehensive understanding.^[12] Hopelessness, another prominent symptom of depression, has been suggested to influence lipid profile levels. A study by Fawcett et al. observed a potential association between hopelessness and elevated triglyceride and LDL levels.^[13] Moreover, higher hopelessness scores correlated with a higher LDL to HDL ratio, indicating an unfavorable lipid profile.^[14,15] These findings suggest a possible link between hopelessness and cardiovascular health, considering the established role of elevated triglycerides (TG) and LDL as risk factors for heart disease.^[16] Cholesterol, a critical component of the lipid profile, plays a key role in various bodily processes. LDL cholesterol (LDL-C), often referred to as “bad cholesterol,” transports cholesterol to peripheral tissues and contributes to atherosclerosis and cardiovascular diseases. Conversely, HDL cholesterol (HDL-C), known as “good cholesterol,” helps eliminate excess cholesterol, thereby reducing cardiovascular risk. Imbalances in LDL-C and HDL-C levels are associated with increased cardiovascular risks among individuals with depression.^[17,18]

MATERIAL AND METHODS

The primary objective of this case-control observational study is to investigate the potential of serum lipids as peripheral markers for depression. In addition, the study aims to explore the associations between serum lipids and two key aspects of depression: suicidal ideation and anhedonia. The study was conducted at a tertiary care center over 18 months. The study population consisted of patients diagnosed with depression, aged 18–60 years, attending the outpatient and inpatient departments. A sample size of 200 subjects, with 100 cases and 100 age matched controls, was selected for the study.

“Data analysis was performed using Statistical Package for the Social Sciences, version 28. Various statistical tests, including unpaired t-test, Chi-square, one-way Analysis of Variance (ANOVA), Analysis of Covariance (ANCOVA), Partial correlation analysis, and post hoc analysis-pairwise comparison (Bonferroni correction), were employed to analyze the data. P < 0.05 was considered significant for t-test, Chi-square, one-way ANOVA, and ANCOVA. However, the P-value for the post hoc analysis-pairwise comparison of lipids and depression - Bonferroni correction was done, and a corrected P-value of 0.002 was obtained. Corrected P-value = original alpha level (0.05)/No. of comparisons (6/lipid parameter × 4 parameters).

The sample size calculation was performed using the formula: N = (Z^2 × P × (1–P))/d^2, where Z^2 represents the table value of the alpha error from the Standard Normal Distribution table, which is 1.96 ×1.96, equaling 3.84. The desired power (P) was set at 0.05, and (1-P) was calculated as 0.95. The precision error of estimation (d) was determined as 5%, resulting in d^2 being 0.0025. Therefore, N = (3.84 × 0.05 × 0.95)/0.0025, which equals 73 (rounded off to 75). However, to increase the power of the study, a sample size of 100 patients per group was used, leading to a total sample size of 200 patients selected for the study. Cases were selected from the inpatient department and outpatient department of the psychiatry department at the medical college, while controls were recruited from attendants accompanying the patients and medical college staff who met the inclusion and exclusion criteria. Blood samples for serum lipid analysis were collected in the early morning after an overnight fast, and the blood was processed in the central laboratory of the medical college. “Outpatients were instructed to come to the hospital after an overnight fast of 8 h.”

Inclusion criteria for cases required patients to be diagnosed with depression using the International Classification of Diseases-10-Diagnostic Criteria for Research, diagnostic criteria, and be between 18 and 60 years of age. (We had taken patients with a primary diagnosis of depression. We also included the patients with co-morbid anxiety as part of depressive symptoms). Controls included healthy individuals within the same age range. Exclusion criteria for both cases and controls involved participants with co-morbid psychiatric illnesses (except depression and depression with comorbid anxiety) or recent substance use disorders except tobacco use disorders, active unstable medical conditions, participants on lipid-lowering agents, and those with a body mass index (BMI) >30.

The methodology involved recruiting eligible participants who provided written informed consent. Clinical interviews were conducted, and height, weight, and BMI measurements were taken. The severity of depression was assessed using the Hamilton Depression Rating Scale-17 (HAMD-17) item scale, while suicidal ideation and anhedonia were evaluated using the Modified Scale for Suicidal Ideation (MSSI) and Snaith-Hamilton Pleasure Scale-Clinician administered (SHAP-C), respectively. Laboratory procedures were conducted to measure plasma levels of TG, TC, and HDL cholesterol.

RESULTS

The cases and controls had an average age of 38 years, and gender distribution was consistent between the two groups, comprising 44% males and 56% females in both. The mean BMI among the cases and the controls was 23.5. However, marital status did exhibit significance (P = 0.003 – Chi-square test), with most controls being married (72%) compared to cases (52%). Employment and education status did not significantly differ between cases and controls. We used the HAMD-17 item to quantify the severity of depression. In the case group, the mean HAMD score was 20.32, whereas it was 4.28 in the control group. Suicidal ideation in the case group was assessed using the MSSI, revealing a mean score of 14.84, with most cases (49%) reporting mild/moderate suicidal ideation. In addition, we evaluated hopelessness using the SHAPS-C in the case group, which yielded a mean score of 35.16.

Regarding the serum lipid levels, the case group demonstrated a statistically significant difference with the lower mean serum TC levels in comparison to the control group (153.27 mg/dL vs. 171.34 mg/dL, P < 0.01*- unpaired t-test). However, there were no statistically significant variances in other lipid parameters, including TG, HDL-C, and LDL-C, between the two groups.

In the case group, serum lipid parameters were analyzed using one-way ANOVA, stratified by severity levels of depression (HAMD-17 item score). Significant variations were found in TC, TG, and LDL levels across different depression severity (P < 0.01*). According to post hoc analysis, individuals with severe and very severe depression exhibited higher lipid levels compared to those with mild or moderate depression. However, no significant differences were observed in serum HDL-C levels among these groups (P = 0.14), as mentioned in Table 1. Post hoc analysis – pairwise comparison in the case group, with a significance threshold of <0.002- corrected P-value (Bonferroni correction), highlighted substantial differences in lipid parameters based on depression severity. Comparison between mild to very severe depression showed high significance (P ≤ 0.002), emphasizing the impact of mental health severity on lipid profiles as mentioned in Table 2.

Tables 3 and 4 collectively indicate that following rigorous statistical analyses—ANCOVA for suicidal ideation and Partial Correlation for anhedonia — no significant relationships were observed between various lipid parameters and both suicidal ideation and anhedonia.

Table 1 shows the analysis of serum lipid parameters in the case group (using one-way ANOVA) and stratified by the various severity levels of depression as measured by the HAMD-17 item score, revealing significant variations. Statistically significant differences were observed in serum TC, serum TG, and serum LDL levels among individuals with different severity levels of depression.

Table 2 shows the post hoc analysis of different depression severity levels in relation to serum cholesterol levels. The most significant variations were observed when comparing the following pairs: mild to very severe depression, moderate to severe depression, moderate to very severe depression, and severe to very severe depression. In all these cases, except for HDL, all lipid parameters exhibited high statistical significance (P ≤ 0.05).

DISCUSSION

Our analysis of serum lipid profiles revealed significant distinctions between the case and control groups. Individuals diagnosed with depression exhibited notably lower TC levels compared to the control group. This finding aligns with the previous research by Terao et al.^[31] and Khalid et al.,^[32] suggesting a potential link between low TC and depression. However, it contrasts with the observations of Olusi and Fido,^[11] where no such correlation was identified.

Several explanations can be explored to understand the observed association between low serum cholesterol and depression. Cholesterol plays a critical role in cell membrane structure and influences cellular signaling processes. Alterations in cholesterol levels may modulate serotonin, a neurotransmitter implicated in mood regulation and depression. Reduced cell membrane cholesterol could lead to decreased exposure to serotonin receptors, resulting in poorer serotonin uptake and its reduced availability in the brain.^[33,34] Dysregulation of the lecithin-cholesterol acyltransferase enzyme, involved in cholesterol metabolism, may also contribute to altered peripheral serum cholesterol levels. Dysfunction in serotonin release and abnormalities in lipid metabolism may be interconnected with depression, potentially leading to changes in serum lipid profiles.^[35] The association between low serum lipid levels and depression might also be attributed to alterations in the HPA axis, known to be dysregulated in depression.^[20] Dysfunctional HPA axis activity can lead to changes in lipid metabolism and potentially contribute to the severity of depressive symptoms. Conversely, increased stress-induced secretion of cholesterol in the liver, derived from the release of free fatty acids in adipose tissues, may contribute to higher serum cholesterol levels in some individuals with depression.^[36] Dysfunctionality of sterol carrier protein 2, involved in cholesterol metabolism, could also play a role.^[37]

CONCLUSION

The present study indicates a potential association between low serum lipid levels, specifically TC and LDL-C, and depressive symptoms. The findings contribute to the growing body of literature on the relationship between lipid metabolism and depression, supporting the notion that disturbances in cholesterol metabolism may play a role in the pathophysiology of depression. However, the lack of a significant correlation between serum lipid levels and anhedonia suggests that different biological mechanisms may underlie this specific symptom of depression.