Association between lipid parameters and severity of depressive symptoms in patients with first-diagnosed drug-free major depressive disorder

doi:10.21203/rs.3.rs-3956327/v1

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Association between lipid parameters and severity of depressive symptoms in patients with first-diagnosed drug-free major depressive disorder

https://doi.org/10.21203/rs.3.rs-3956327/v1

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Objective

The association between lipid biomarkers and the severity of depressive symptoms remains uncertain in patients with major depressive disorder (MDD), as previous findings have been debatable. The objective of this research was to examine the correlation between lipid parameters and the severity of depressive symptoms in patients with first-diagnosed drug-free (FDDF) MDD in Chinese.

Methods

From 2016 to 2018, a total of 1718 individuals diagnosed with FDDF MDD were recruited. Detailed sociodemographic details and anthropometric measurements were gathered from each patient. An assessment of anxiety and depressive symptoms was conducted using the Hamilton Anxiety Scale (HAMA) and the 17-item Hamilton Rating Scale for Depression (HAMD-17), respectively. Furthermore, thyroxine hormones, fasting blood glucose (FBG) levels, and lipid profiles were ascertained using blood samples taken by a trained clinician. Univariate and multivariate linear regression analyses were then employed to ascertain if there was an association between patient lipid profiles and depressive symptom severity. Additionally, a two-segmental linear regression analysis was used to investigate threshold effects.

Results

Subsequent to adjusting for covariates, multivariate linear regression analysis unequivocally demonstrated a positive correlation between total cholesterol (TC), triglyceride (TG), and low-density lipoprotein cholesterol (LDL-c), but not high-density lipoprotein cholesterol (HDL-c), and the manifestation of depressive symptoms in patients with FDDF MDD. Intriguingly, the relationship between TC, TG, LDL-c, and depressive symptoms exhibited a non-linear pattern. By employing a two-segmental linear regression model, distinct inflection points at 6.17 mmol/l for TC, 1.80 mmol/l for TG, and 4.12 mmol/l for LDL-c were unveiled. At values higher than each inflection point, we observed a positive association between TC, TG, LDL-c, and depressive symptoms (all P < 0.05). However, this relationship between lipids and depressive symptoms appears to plateau at values higher than each inflection point (all P > 0.05). Notably, the correlation between HDL-c and depressive symptoms, on the other hand, appeared to exhibit a "U"-shaped pattern, where 1.10 mmol/l was found to be optimal.

Conclusion

Our investigation shed light on the intricacies regarding the association between lipid markers (TC, TG, LDL-c, and HDL-c) and the severity of depressive symptoms in patients with FDDF MDD, thereby offering valuable insights into the underlying mechanisms involved.

Health sciences/Biomarkers

Health sciences/Diseases

Health sciences/Medical research

Health sciences/Risk factors

association

lipid parameters

cholesterol

depressive symptoms

major depressive disorder

Major depressive disorder (MDD) is a prevalent mental illness affecting approximately 185 million individuals worldwide [1]. This condition is characterized by enduring feelings of low mood and/or diminished interest in previously enjoyable activities, along with several other symptoms, notably recurrent suicidal ideation [1]. Individuals afflicted with MDD experience high levels of stigma and a heightened susceptibility to various comorbidities, such as obesity, type 2 diabetes, and heart disease [2]. In addition to these health challenges, depression adversely affects interpersonal relationships, educational pursuits, and one’s ability to work [3, 4]. Indeed, the enormous economic and societal cost of MDD-associated disability is well documented, and that is not to mention the emotional burden to the individual. For example, depression is estimated by the World Health Organization (WHO) to account for around 10% of the global burden of non-fatal illnesses, making MDD the second most prevalent cause of disability on a global scale, projected to surpass all other diseases by 2030 [5]. Considering the substantial medical and healthcare implications imposed by depression, there is a pressing imperative for continued comprehensive investigation of its pathophysiology as well as potential biomarkers of its presence.

MDD is a condition that arises from the intricate interplay of environmental, genetic, biological, and psychological factors [6]. Despite escalating scientific inquiries into the processes affecting depression risk, no laboratory biomarkers for depression presently exist, with the condition exclusively being diagnosed and understood through fairly blunt survey measures. There has been a burgeoning interest in the potential association between plasma lipid composition and depressive states in recent years. Extensive research has revealed an increased prevalence of dyslipidemia in individuals afflicted with depression compared to the rest of the population [7]. Despite this, inconsistencies in findings plague the current literature. Some studies have documented a positive correlation between lower total cholesterol (TC) plasma concentrations and the presence of depressive symptoms [8, 9]. while others have found no relationship or, even, an absence of correlation [10–12]. Similar inconsistency has been observed when examining low-density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol (HDL-c), and triglycerides (TG) in relation to depressive symptoms [13–15]. These inconsistent findings suggest a level of complexity in the relationship between lipid biomarkers and depressive symptoms that previous studies were unable to identify. Perhaps, therefore, methodological differences in these studies, such as variations in study design and the utilization of diverse depression rating scales, may have been a cause of confounding findings. Equally, participant medication history, ethnicity, age, and dietary patterns could also have contributed to the observed inconsistencies.

The study of first-diagnosed and drug-free (FEDN) MDD patients offers a significant advantage over the study of broader depressed populations due to limiting potential confounding variables, including differences in medication history and disease duration [16]. Although previous investigations have statistically compared lipid profiles between MDD patients and healthy controls, limited attention has been given to thoroughly examining the correlation between these parameters and the severity of depressive symptoms [17]. Furthermore, a majority of prior studies have focused on hospitalized patients or those under medication, which themselves can influence lipid levels as well as dietary and exercise habits [8–15]. The primary objective of this study was to examine the connection between lipid profiles and the severity of depressive symptoms among Chinese Han FDDF MDD patients while utilizing a larger sample size (1718 individuals) than prior studies.

2.1. Study design and participants

This study was authorized by the Institutional Review Board (IRB) of the First Clinical Medical College at Shanxi Medical University under the approval number 2016-Y27. It was carried out in adherence to the regulations outlined in the Declaration of Helsinki. Before the study started, each participant was provided with comprehensive information regarding the purpose and procedures of the investigation. Written consent forms were obtained from all enrolled patients.

In this cross-sectional study, consecutive patients diagnosed with FDDF MDD were recruited between 2016 and 2018 at the First Hospital of Shanxi Medical University in Taiyuan, Shanxi Province, China. All medical and psychological tests were conducted by trained healthcare professionals. To encourage continued participation and adherence, participants were remunerated and given a comprehensive report regarding their medical results.

In all, 1718 patients with FDDF MDD were recruited and selected with exclusion criteria in this investigation, comprising 1130 women and 588 men. All patients met the threshold for the diagnostic criteria laid out in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM IV-TR). For inclusion, patients had to meet the following criteria: (1) Han Chinese ethnicity; (2) ranging from 18 to 60 years of age; (3) currently experiencing depressive symptoms and in their first episode; (4) no prior usage of antidepressant medication; and (5) obtaining a 17-item score equal to or exceeding 24 on the Hamilton Depression Scale (HAMD-17). On the other hand, exclusion criteria included: (1) pregnancy or lactation (n = 10); (2) presence of an Axis I mental disorder other than MDD (n = 15); (3) history of substance abuse or a history of alcoholism (n = 9); (4) presence of other physical illnesses, including cancer, chronic infection, brain injury, epilepsy, or stroke (n = 9); and (5) consideration of other factors (n = 14).

2.2. Socio-demographic characteristics and anthropometric data

Anthropometric and detailed socio-demographic information was systematically gathered from each participant via a standardized questionnaire. Assessed variables included age, sex, educational attainment, marital status, and duration of the MDD episode. Regarding educational attainment, individuals were classified into one of four categories: postgraduate, college, high school graduate, and junior high school graduate. Marital status was dichotomized into two categories: single, divorced, widowed, and married.

After a prescribed resting period of no less than 15 minutes in a seated posture, diastolic and systolic blood pressure (DBP and SBP, respectively) were taken repeatedly on the right upper arm with a standard mercury sphygmomanometer. Subsequently, the average of these readings was calculated. Additionally, each patient provided accurate anthropometric measurements encompassing their height in meters (m) and weight in kilograms (kg), which were subsequently used for the computation of body mass index (BMI) [16]. The formula used to determine the BMI was BMI = weight/(height)².

2.3. Clinical psychological assessment

The Hamilton Depressive Rating Scale (HAMD-17) was utilized to gauge the extent of depressive symptoms; a score of more than 24 on the HAMD-17 represents severe depression [18]. The overall degree of anxiety symptoms was determined employing the Hamilton Anxiety Rating Scale (HAMA) [19]. Higher scores on the scale correspond to more severe anxiety symptoms, with the total score spanning 0 to 56.

Two licensed psychiatrists with at least five years of clinical experience administered these diagnostic assessments. Repeated assessments using these scales yielded a correlation coefficient exceeding 0.8, demonstrating a robust level of inter-observer reliability.

2.4. Blood samples

After fasting for 8–12 hours, every participant provided a venous blood sample, which was collected and analyzed at the hospital's laboratory department. Blood biomarkers were assessed on the same day as sample collection. These included thyroid-stimulating hormone (TSH), anti-thyroglobulin (TgAb), triglycerides (TG), total cholesterol (TC), fasting blood glucose (FBG), low-density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol (HDL-c), free triiodothyronine (FT3), free thyroxine (FT4), and thyroid peroxidase antibody (TPOAb).

2.5. Data handling and regression analysis

Across all participants, categorical data was presented as percent and frequency (%), while continuous parameters were shown as mean ± standard deviation (SD). The association between lipids and depressive symptoms was investigated using univariate and multivariate linear regression models. Using the variance inflation factor (VIF), independent variables were considered for multicollinearity; variables with a VIF value larger than 5.0 were excluded from the final model. Every covariate was incorporated into the model separately. Consequently, possible confounders were kept in the final version if they produced a change in the estimated relationship between lipid profiles and depressive symptoms of greater than 10% or showed a p-value in the univariate analysis that was less than 0.10 [20]. In following the reporting guidelines for STROBE (Strengthening the Reporting of Observational Studies in Epidemiology), three distinct linear regression approaches were applied to look into the relationship between lipid profiles and depressive symptoms [21]. These included an unadjusted model as well as a minimally adjusted model (Model I), which adjusted for gender and age, and a fully adjusted model (Model II), which adjusted for lipid parameters, age, sex, education, marital status, HAMA scores, BMI, SBP, DBP, TSH, TPOAb, TgAb, and FBG. Utilizing a curve smoothing plot, the correlation between lipid profiles and depressive symptoms was also investigated. In the event that a non-linear correlation was identified, a two-piecewise linear regression approach derived from generalized estimating equations (GEE) was employed for determining the threshold effect [22]. The recursive method was performed to calculate the breakpoint, and the maximum model likelihood was applied for further analysis. Statistical analyses were performed using R package version 4.3.0 (http://www.r-project.org, The R Foundation) and EmpowerStats (http://www.empowerstats.com). A p-value of under 0.05 was deemed statistically significant for each analysis.

3.1. Patient enrolment and baseline characteristics

The study encompassed 1718 individuals diagnosed with FDDF MDD. The mean age of the respondents was 34.87 ± 12.43 years, with 588 (34.23%) being males and 1130 (65.77%) females. The subjects exhibited a mean HAMD score of 30.30 ± 2.94. Detailed patient sociodemographic characteristics, medical history, lipid profiles, thyroid hormone levels, FBG values, BMIs, and blood pressure readings are provided in Table 1.

Table 1

The results of the univariate analysis of HAMD score
HAMD score	Statistics	β (95% CI)	P-value
Age (years)	34.87 ± 12.43	0.02 (0.00, 0.03)	0.006
Duration of illness (months)	6.31 ± 4.73	0.06 (0.03, 0.09)	< 0.001
Sex (n, %)
Male	588 (34.23%)	0 (reference)
Female	1130 (65.77%)	0.02 (-0.27, 0.32)	0.883
Education (n, %)
Junior high school	413 (24.04%)	0 (reference)
Senior high school	760 (44.24%)	-0.16 (-0.51, 0.19)	0.379
College	449 (26.14%)	-0.37 (-0.76, 0.02)	0.064
Postgraduate	96 (5.59%)	-0.06 (-0.71, 0.59)	0.855
Marital status (n, %)
Single	502 (29.22%)	0 (reference)
Married	1216 (70.78%)	0.26 (-0.04, 0.57)	0.090
HAMA	20.80 ± 3.47	0.52 (0.49, 0.55)	< 0.001
TSH (uIU/ml)	5.07 ± 2.56	0.55 (0.50, 0.59)	< 0.001
TGAb (IU/l)	90.02 ± 238.34	0.001 (0.001, 0.002)	< 0.001
TPOAb (IU/l)	72.27 ± 163.77	0.003 (0.002, 0.003)	< 0.001
FT3 (pmol/l)	4.90 ± 0.72	0.13 (-0.06, 0.32)	0.186
FT4 (pmol/l)	16.70 ± 3.10	0.01 (-0.04, 0.05)	0.766
FBG (mmol/l)	5.40 ± 0.65	1.08 (0.87, 1.29)	< 0.001
TC (mmol/l)	5.25 ± 1.11	1.49 (1.38, 1.59)	< 0.001
HDL-c (mmol/l)	1.22 ± 0.29	-1.48 (-1.96, -1.00)	< 0.001
TG (mmol/l)	2.17 ± 0.99	0.48 (0.34, 0.62)	< 0.001
LDL-c (mmol/l)	2.98 ± 0.86	1.33 (1.18, 1.48)	< 0.001
BMI (kg/m²)	24.37 ± 1.92	0.08 (0.00, 0.15)	0.038
SBP (mmHg)	119.48 ± 10.91	0.08 (0.06, 0.09)	< 0.001
DBP (mmHg)	75.95 ± 6.74	0.10 (0.08, 0.12)	< 0.001
Note: The variables are presented as n (%) or the mean ± SD, HAMD: 17-item Hamilton Rating Scale for Depression; HAMA: 14-item Hamilton Anxiety Rating Scale; BMI: body mass index; FBG: fasting blood glucose; TC: total cholesterol; TG: triglyceride; HDL-c, high-density lipoprotein cholesterol; LDL-c: low-density lipoprotein cholesterol; TSH: thyroid-stimulating hormone; FT3: free triiodothyronine; FT4: free thyroxine; TGAb: thyroglobulin antibody; TPOAb: thyroid peroxidase antibody; SBP: systolic blood pressure; DBP: diastolic blood pressure.

3.2. Univariate analysis of depressive symptoms

The univariate analysis outcomes pertaining to depressive symptoms are presented in Table 1. Notably, several variables exhibited a significant correlation with depressive symptoms. Age (β = 0.02, 95% CI: 0.00–0.03), duration of illness (β = 0.06, 95% CI: 0.03–0.09), HAMA (β = 0.52, 95% CI: 0.49–0.55), TSH (β = 0.55, 95% CI: 0.50–0.59), TGAb (β = 0.001, 95% CI: 0.001–0.002), TPOAb (β = 0.003, 95% CI: 0.002–0.003), FBG (β = 1.08, 95% CI: 0.87–1.29), TC (β = 1.49, 95% CI: 1.38–1.59), TG (β = 0.48, 95% CI: 0.34–0.62), LDL-c (β = 1.33, 95% CI: 1.18–1.48), BMI (β = 0.08, 95% CI: 0.00–0.15), SBP (β = 0.08, 95% CI: 0.06–0.09), DBP (β = 0.10, 95% CI: 0.08–0.12) all demonstrated positive correlations with depressive symptoms (all P < 0.05). Conversely, HDL-c levels exhibited a negative correlation with depressive symptoms (β = -1.48, 95% CI: -1.96 – -1.00, P < 0.001).

3.3. The correlation between lipid parameters and depressive symptoms

For researching the associations between lipid features and depressive symptoms, a linear regression approach was carried out in the initial investigation. Both the results of the adjusted and unadjusted models are presented together in Table 2. In the unadjusted model, TC, TG, and LDL-c demonstrated positive correlations with depressive symptoms (all P < 0.001). These correlations remained significant (all P < 0.001) when controlling for gender and sex (Model I) and when controlling for age, sex, education, marital status, HAMA, SBP, DBP, TSH, TGAb, TPOAb, FBG, BMI, and other lipid parameters excluding the variable under consideration (Model II). Conversely, HDL-c exhibited a negative association with depressive symptoms in both the unadjusted and minimally adjusted models (all P < 0.001). However, this correlation was weakened and lost significance after full adjustments (β = 0.25, 95% CI: -0.13–0.63, P = 0.201).

Table 2

Relationship between lipid parameters and HAMD score in different models
Variable		Unadjusted Model		Model Ⅰ		Model Ⅱ
Variable	N	β (95%CI)	P-value	β (95%CI)	P-value	β (95%CI)	P-value
TC (mmol/l)	1718	1.49 (1.38, 1.59)	< 0.001	1.48 (1.38, 1.59)	< 0.001	0.93 (0.82, 1.03)	< 0.001
HDL-c (mmol/l)	1718	-1.48 (-1.96, -1.00)	< 0.001	-1.46 (-1.93, -0.98)	< 0.001	0.25 (-0.13, 0.63)	0.201
TG (mmol/l)	1718	0.48 (0.34, 0.62)	< 0.001	0.48 (0.34, 0.62)	< 0.001	0.19 (0.08, 0.29)	< 0.001
LDL-c (mmol/l)	1718	1.33 (1.18, 1.48)	< 0.001	1.32 (1.17, 1.47)	< 0.001	0.66 (0.53, 0.79)	< 0.001
Abbreviations: CI, confidence interval; Unadjusted Model adjusted for none; Model Ⅰ adjusted for age, sex; Model Ⅱ adjusted for age, sex, education, marital status, HAMA, BMI, SBP, DBP, TSH, TGAb, TPOAb, and FBG.

3.4. Analysis of non-linearity

After considering various factors such as age, sex, education, marital status, HAMA, BMI, SBP, DBP, TSH, TGAb, TPOAb, FBG, BMI, and lipid parameters, excluding the variable itself, it was determined that the relationship between lipid parameters and depressive symptoms would not follow a linear pattern (all P for nonlinearity < 0.05). The findings of this investigation are presented in Table 3 and Figs. 1 (A, B, C, and D). TC, TG, and LDL-c all demonstrated saturation effects regarding their association with depressive symptoms. Inflection points were identified in a two-stage linear regression technique to be 6.17 (mmol/l), 1.80 (mmol/l), and 4.12 (mmol/l), respectively. On the left flank of the turning point, TC, TG, LDL-c, and depressive symptoms showed a positive link (all P < 0.05), but a lack of association existed on the right side (all P > 0.05). Interestingly, the relationship between HDL-c and depressive symptoms followed a "U"-shaped pattern, with an inflection point for HDL-c at 1.10 mmol/l. On the left side of the turning point, there had been a negative correlation (β = -1.21, 95% CI: -2.21–0.21, P = 0.018), while a positive correlation was found on the right side (β = 0.94, 95% CI: 0.36–1.52, P = 0.002).

Table 3

The results of two-segmental linear regression model
	TC (mmol/l)		HDL-c (mmol/l)		TG (mmol/l)		LDL-c (mmol/l)
	β (95% CI)	P-value	β (95% CI)	P-value	β (95% CI)	P-value	β (95% CI)	P-value
Inflection point	6.17		1.10		1.80		4.12
< inflection point slope 1	1.26 (1.13, 1.39)	< 0.001	-1.21 (-2.21, -0.21)	0.018	0.92 (0.53, 1.30)	< 0.001	0.79 (0.64, 0.94)	< 0.001
≥ inflection point slope 2	-0.14 (-0.43, 0.15)	0.348	0.94 (0.36, 1.52)	0.002	-0.01 (-0.15, 0.14)	0.924	-0.14 (-0.68, 0.40)	0.616
slope 2 – slope 1	-1.40 (-1.75, -1.04)	< 0.001	2.15 (0.79, 3.52)	0.002	-0.92 (-1.39, -0.45)	< 0.001	-0.93 (-1.53, -0.32)	0.003
predicted at inflection point	32.14 (31.93, 32.35)		29.83 (29.58, 30.07)		30.49 (30.26, 30.72)		32.07 (31.81, 32.33)
Log likelihood ratio test	< 0.001		0.002		< 0.001		0.003
Effect: HAMD score; Cause: lipid parameters; adjusted for age, sex, education, marital status, HAMA, BMI, SBP, DBP, TSH, TGAb, TPOAb, and FBG.
Slope 1 and slope 2 are the slope coefficients for the segment before and after the inflection point.

To the greatest of our expertise, this is the first research investigation to use a large number of participants to explore the association between lipid markers and the severity of depressive symptoms in patients with FDDF MDD in China. The initial findings demonstrated a positive connection between TC, TG, and LDL-c levels and depressive symptoms, even after adjusting for potential confounding factors. However, no discernible correlation was observed between HDL-c and depressive symptoms. A nonlinear relationship was identified between the severity of depressive symptoms and the concentrations of TC, TG, and LDL-c, with inflection points identified at 6.17 mmol/l, 1.80 mmol/l, and 4.12 mmol/l, respectively. Specifically, for each of these parameters, a positive correlation depressive symptom was observed at values below the inflection point, with no significant correlation being detected to the above of the points. This suggested a saturation-like effect, with TG, TC, and LDL-c above a certain level no longer being associated with worse symptom profiles. Equally, the correlation between HDL-c and depressive symptoms also exhibited a nonlinear pattern. This was characterized by a "U"-shaped correlation, with a turning point identified at 1.10 mmol/l. A negative correlation appeared at HDL-c levels below this turning threshold, but a positive correlation was obvious for those above it. These findings unveil a crucial link between lipid parameters and the severity of depressive symptoms in FDDF MDD patients and provide novel insights requiring further clinical and pre-clinical investigation.

Investigating the relationship between different diseases and plasma lipid composition has gained more attention in recent years. In clinical practice, biomarkers such as LDL-c, HDL-c, TC, and TG are commonly employed to assess lipid profiles and identify individuals at risk for cardiovascular disease [23]. Extensive research has elucidated a connection between depression and lipid disturbances, and depressed patients are more susceptible to developing cardiovascular disorders [24]. Furthermore, compared to healthy controls, a recent study showed that individuals with schizophrenia and various mood disorders consistently had a decrease in HDL-c and elevated levels of TC, LDL-c, TG, and glucose [25]. Both hyperlipidemia and depression are well-documented risk factors for cardiovascular disease and significantly heighten the likelihood of myocardial infarction and mortality among individuals with coronary heart disease [26].

There remains a lack of extensively validated predictive laboratory biomarkers for depression, prompting the inquiry as to whether depression might be linked to an altered plasma lipid profile. However, anomalous lipid biosynthesis stands as one conceivable pathophysiological mechanism underlying depressive symptoms [27], making lipid profile testing a conceivable candidate. Gene polymorphisms in lipid metabolism-related genes have been implicated in depression risk, further indicating a causal role for lipids in the pathophysiology of depressive symptoms [28]. Evidence suggests poor metabolic health can not only impact the overall depression prognosis but also heighten the vulnerability to premature mortality in individuals presenting with depressive symptoms [29]. Considering the fact that dyslipidemia is more common in depressed individuals and that MDD, cardiovascular, and cerebrovascular diseases share many of the same genetic risk factors, it is plausible that a lipid pathway specific to the disease is involved in the pathophysiology of depression [30].

In considering the correlation between lipids and MDD, it is noteworthy that the human brain encompasses 20% of the body's total cholesterol, with myelin-forming oligodendrocytes harboring approximately 70% of this cholesterol content [31]. The involvement of myelinating oligodendrocytes in various aspects of neuronal function, such as information processing speed, protection against oxidative stress, and maintenance of blood-brain barrier integrity, has been well-established [32]. Perturbed neuron myelination and oligodendrocyte function have been observed in several psychiatric disorders. Specifically, in MDD, reduced myelination has been observed [33]. Furthermore, it is worth noting that the fluidity of the plasma membrane is influenced by the concentration of cholesterol. This, in turn, exerts regulatory control over membrane-bound proteins, ion channels, and subsequent synaptic transmission [34]. Previous research has also highlighted potential mechanisms underlying the link between specific lipids and the severity of depression symptoms. For example, pro-atherogenic lipids (LDL-c, TC, and TG) and anti-atherosclerotic lipids (HDL-c) have been shown to exert distinct influences on serotonin levels [35], potentially explaining their differential effects on depression risk.

In this study, we observed positive correlations between depressive symptoms and TC, TG, and LDL-c, while noting a negative correlation between depression severity and HDL-c (when HDL-c levels fell below 1.10 mmol/l), aligning with the findings of prior research [23, 26]. A study conducted previously demonstrated a positive association between TC and LDL-c plasma concentration and the risk of depression among individuals suffering from psychotic disorders [17]. This association remained robust even after accounting for potential confounding factors, including BMI, smoking habits, and the use of dyslipidemia-related antipsychotic agents. Furthermore, Brunner et al. unveiled a positive correlation between TC and TG plasma concentrations and the risk of suicide attempts within the past 12 months among those afflicted with depression [36]. Liang et al. conducted a study examining Chinese older individuals and discovered that the presence of elevated depressive symptoms was co-morbid with a serum lipid profile characterized by heightened TC, TG, LDL-c and low HDL-c levels, often meeting the threshold for dyslipidemia [37].

The precise mechanisms underlying lipid dysregulation in MDD remain insufficiently understood. Depressive symptomatology may give rise to alterations in health behaviors, such as altered dietary habits and physical activity, potentially influencing the relationships between serum cholesterol components and depressive symptoms. For example, low intake of long-chain polyunsaturated fatty acids, which has frequently been observed in depression, may be the cause of the correlation between reduced HDL-c levels and long-term depression [38]. Furthermore, individuals diagnosed with depression have been reported to consume foods with a higher energy density compared to their healthy counterparts [39]. Lipid profile differences seen in MDD patients may also be attributable to other poor lifestyle habits like a sedentary lifestyle, excessive alcohol consumption, and poor nutrition [40]. In addition, MDD may influence lipid profiles through increased activity of the axis, sympathetic nervous system (SNS), and hypothalamic-pituitary-adrenal (HPA) axis [41]. Elevated cortisol levels trigger an increase in the circulation of free fatty acids, consequently encouraging the liver's generation of very low-density lipoprotein (VLDL), thus leading to an upsurge in TG concentrations [39]. Another mechanism linking depression and dyslipidemia is the activation of inflammatory pathways [42]. Numerous investigations have found elevated levels of certain inflammatory cytokines to be positively correlated with depression [43]. Increased inflammation contributes to a decline in the activity of the lecithin cholesterol acyltransferase enzyme, thereby resulting in reduced HDL formation [44]. Additionally, the presence of inflammatory cytokines, such as TNFa and IL-1b, is also known to trigger hepatic fatty acid synthesis, increasing TG levels [45].

Despite some convincing previous findings, the existing literature does present some contradictions regarding the connection between depression and blood lipid levels. Several prior investigations have established a connection between lower TC levels and depression [9, 11, 13, 14]. Conversely, as previously mentioned, other reports have suggested a potential association between depression and elevated serum cholesterol [46–48]. Inconsistencies in findings were also observed in relation to less extensively studied lipid measures such as LDL-c, HDL-c, and TG [13–15]. The correlation between depression and HDL-c has been the subject of numerous prior investigations, with varying degrees of success [49–51]. While several research [49, 51] have linked low HDL-c levels to depression, just one study [51] has connected high HDL-c levels to depression. These inconsistent findings could be attributed to several factors. Firstly, this disparity may stem from variations in the clinical condition of the studied samples, such as drug naivety or severity [52]. Second, it is plausible that the inclusion of subjects with other mental disorders, such as psychotic symptoms [17, 25], in prior studies may have introduced clinical confounders influencing study results. Lastly, it is noteworthy that previous studies did not investigate the non-linear association between lipids and depressive symptoms. Our research has made significant strides in this regard. Given that our findings revealed a non-linear relationship between TC, TG, LDL-c, and depressive symptoms, our results may help explain previously contradictory findings.

This study has a number of limitations to take into account. First and foremost, it is crucial to acknowledge that the individuals included in our investigation originated from the Chinese Han population, and they were only brought in through an outpatient visit. Consequently, it is imperative to validate our findings across more diverse populations with distinct ethnic and clinical characteristics. Second, it's critical to recognize that the cross-sectional design of our research design inherently restricts our capacity to determine a cause-and-effect link between lipids and depressive symptoms in MDD patients. Therefore, while our results provide valuable insights, they should not be considered to be indicative of a causal relationship between lipids and depression. Furthermore, it is essential to corroborate these findings through longitudinal and prospective studies conducted across different geographical populations. Thirdly, it is important to note that only first- diagnosed MDD individuals without a history of medication-untreated depression symptoms were included in the study's participant pool. While this confers the advantage of minimizing potential confounds, caution must be exercised when generalizing our findings to broader populations of MDD patients. Subsequent investigations ought to cover a wider spectrum of MDD individuals and different stages of the illness. Fourth, the present study did not capture certain confounding factors that could potentially influence depression, such as socioeconomic status, alcohol consumption, smoking habits, or familial income. To confirm our findings, future research should take a broader range of confounding variables into account. Furthermore, this could provide useful knowledge regarding the pathophysiology connecting lipid biomarkers and depression symptom severity. Fifth, it should be noted that the severity of depressive symptoms among the MDD patients enrolled in this study was considerable, as evidenced by HAMD scores equal to or greater than 24 and an average HAMA score surpassing 20. Therefore, caution should be exercised when extending the findings of this research to people who suffer from milder kinds of depression.

In conclusion, this study's results demonstrate a non-linear relationship between the levels of TC, TG, LDL-c, and HDL-c and the intensity of depressive symptoms in Chinese patients diagnosed with FDDF MDD. Notably, the inflection point for TC was observed at 6.17 mmol/l, for TG at 1.80 mmol/l, for LDL-c at 4.12 mmol/l, and for HDL-c at 1.10 mmol/l. While the intricate pathophysiological mechanisms linking lipid profiles and depression symptom severity are not yet fully understood, these findings, at least, indicate that TC, TG, LDL-c, and HDL-c levels hold promise as potential biological markers for depression. Further studies should delve into the underlying biological and behavioral mechanisms implicated in this association.

Data availability

The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.

Author contributions

Study Design: Xiangyang Zhang, Xiangdong Du, Junjun Liu. Investigation: Junjun Liu, Fengnan Jia, Xiaobin Zhang, Zhe Li, Libin Xiao, Xiaotang Feng. Analysis and interpretation of data: Junjun Liu, Yang Liu. Drafting of the manuscript: Junjun Liu. Critical revision of the manuscript: Xiangdong Du, Xiangyang Zhang, Libin Xiao. Approval of the final version for publication: Junjun Liu, Xiangdong Du, Xiangyang Zhang.

Acknowledgments

The authors thank the First Clinical Medical College, Shanxi Medical University for the supports.

Conflict of interest

All the authors declare that none of them has a conflict of interest.

Financial Disclosure

This work was supported by the Suzhou Gusu Health Talents Scientific Research Project (Nos. GSWS2021053, GSWS2019070), Key Diagnosis and treatment Program of Suzhou (LCZX202016), the Suzhou clinical Medical Center for mood disorders (Szlcyxzx202109), China Rural Social Survey (Yunnan) (CRSS), the Medical Science and Technology Development Foundation, Nanjing Department of Health (Nos. YKK21216, YKK20184, YKK22264). The funding sources of this study had no role in study design, data collection and analysis, decision to publish, or preparation of the article.

Consent for publication

Written informed consent for publication was obtained from all participants.

Ethics approval and consent to participate

Ethical approval for this study was granted by the Institutional Review Board of the First Hospital, Shanxi Medical University (No. 2016-Y27).

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Association between lipid parameters and severity of depressive symptoms in patients with first-diagnosed drug-free major depressive disorder

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Version 1

Abstract

Objective

Methods

Results

Conclusion

Figures

1. Background

2. Material and methods

2.1. Study design and participants

2.2. Socio-demographic characteristics and anthropometric data

2.3. Clinical psychological assessment

2.4. Blood samples

2.5. Data handling and regression analysis

3. Results

3.1. Patient enrolment and baseline characteristics

3.2. Univariate analysis of depressive symptoms

3.3. The correlation between lipid parameters and depressive symptoms

3.4. Analysis of non-linearity

4. Discussion

Declarations

References

Additional Declarations

Status:

Version 1