Remnant cholesterol (RC), also known as triglyceride-rich lipoproteins, has been gaining increasing attention in recent years due to evidence linking it to cardiovascular disease, diabetes, chronic kidney disease, and other conditions.
A new study suggests that elevated levels of remnant cholesterol in the blood may be associated with an increased risk of depression.
- Adults with depression had higher remnant cholesterol levels compared to those without depression (26.13 vs 23.05 mg/dL).
- Highest remnant cholesterol quartile was associated with a 49% higher odds of depression compared to the lowest quartile.
- Positive association was stronger in men, younger adults, non-obese participants, and those with diabetes.
Source: BMC Psychiatry (2023)
Depression, Inflammation, & Remnant Cholesterol
Depression is a highly prevalent mental health disorder affecting more than 264 million people globally.
In the U.S., around 8% of adults have depression each year.
Depression is associated with substantial disability, reduced quality of life, and increased risk of mortality.
While the causes of depression are multifactorial, chronic inflammation appears to play an important role in the onset and progression of depressive disorders.
Remnant cholesterol is emerging as a key driver of vascular inflammation, leading researchers to hypothesize that elevated RC levels may also be linked to depression pathogenesis.
This large cross-sectional study analyzed data from the National Health and Nutrition Examination Survey (NHANES) to examine whether RC levels are associated with depression prevalence in U.S. adults.
Remnant Cholesterol (RC): What is it?
Remnant cholesterol refers to lipoprotein particles that are formed as intermediate products during the metabolism of triglyceride-rich lipoproteins.
It includes very-low density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), and chylomicron remnants left over following the degradation of triglyceride-rich particles.
Remnant cholesterol (RC) makes up approximately one-third of total circulating cholesterol.
Compared to LDL cholesterol, remnant cholesterol particles are more atherogenic – meaning they are more likely to accumulate in artery walls and drive plaque formation.
A growing body of evidence has linked elevated RC levels to increased risk of cardiovascular events.
Remnant cholesterol has also been implicated in other conditions involving chronic inflammation including fatty liver disease, chronic kidney disease, and diabetes.
However, no previous studies have investigated the potential role of RC in depression.
This represents a significant research gap given the involvement of inflammatory pathways in depression pathophysiology.
NHANES Data: Remnant Cholesterol & Depression
For this analysis, researchers examined data from 8,263 adults aged 18 and older who participated in six 2-year cycles of NHANES between 2005 and 2016.
NHANES is an ongoing survey conducted by the CDC designed to assess the health and nutritional status of adults and children in the U.S.
Depression was assessed using the Patient Health Questionnaire (PHQ-9).
Participants with PHQ-9 scores of 10 or higher were categorized as having depression.
Remnant cholesterol levels were calculated by subtracting HDL and LDL cholesterol from total cholesterol.
The analysis found that weighted mean RC levels were significantly higher among participants with depression compared to those without (26.13 vs. 23.05 mg/dL).
Approximately 5.9% of the study sample had depression based on PHQ-9 criteria.
RC Levels Correlated With Higher Depression Odds
After adjusting for demographic factors, lifestyle variables, and clinical characteristics, the study found a significant positive relationship between RC levels and the likelihood of having depression.
- Compared to the lowest RC quartile, participants in the highest quartile had 49% higher odds of depression.
- The positive association between RC levels and depression remained significant after controlling for confounding factors (age, sex, race, income, education, body mass index, kidney function, etc.).
- There was a clear dose-response relationship, with higher RC levels associated with higher depression odds.
When the analysis was stratified by subgroups:
- The association between RC and depression was stronger in men compared to women. Men in the highest RC quartile had double the odds of depression versus the lowest quartile.
- RC levels were linked to higher depression likelihood in adults under age 60 but not those 60 and over.
- Among non-obese participants (BMI under 30), those in the top RC quartile had 83% higher odds of depression compared to the bottom quartile.
- In patients with diabetes, the highest RC quartile had nearly quadruple the odds of depression compared to the lowest RC quartile.
The positive relationship between RC and depression held up in sensitivity analyses using different cut-points and statistical approaches.
Overall, the results indicate a significant correlation between elevated circulating RC levels and increased odds of depression in the general adult population.
How Could Remnant Cholesterol Cause Depression? (Possible Biological Mechanisms)
This study was not designed to determine causation.
However, the findings are consistent with possible biological pathways that could underlie an etiologic link between high RC levels and depression pathogenesis.
As the researchers highlight, excess RC in the bloodstream promotes vascular inflammation through several mechanisms:
- RC particles easily penetrate the arterial wall where they are engulfed by macrophages and trigger foam cell formation. Foam cells drive release of inflammatory cytokines including interleukin-6 (IL-6).
- IL-6 stimulates the hypothalamic-pituitary-adrenal (HPA) axis which is dysregulated in depression.
- RC likely increases production of pro-inflammatory cytokines that can cross the blood-brain barrier and directly alter the function of neurons and brain cells.
- By promoting vascular inflammation and endothelial dysfunction, RC may impair cerebral blood flow which has been linked to depressive disorders.
Additional longitudinal studies are warranted to further elucidate the causal relationships between RC, inflammation, vascular changes, and depression.
Takeaways: Elevated RC & Depression Risk
This large population-based study provides compelling evidence that elevated RC levels are associated with higher likelihood of depression in U.S. adults.
The findings add to the growing evidence base linking RC to chronic inflammation and metabolic diseases.
This study represents the first analysis of RC levels in relation to depression prevalence.
While provocative, these results alone are not sufficient to demonstrate a causal relationship.
Moving forward, longitudinal cohort studies that measure RC levels long before the onset of depression are needed to determine whether RC is a risk factor for developing depression.
Additionally, trials lowering RC through lifestyle or pharmacological means could provide insight on whether reducing RC levels improves depressive symptoms or lowers depression incidence.
Emerging evidence suggests that using statins for depression may be effective – and statins are known to lower remnant cholesterol (RC).
In the meantime, this study lends support to the theory that inflammation is a common driver of both cardiovascular and psychiatric conditions.
Additional research is warranted to further define the role of cholesterol remnants and other novel inflammatory biomarkers in depression and identify new therapeutic targets.
- Paper: Association of remnant cholesterol with depression among US adults (2023)
- Authors: Yang Wang & Ruhua Shen