Can lowering Low-Density Lipoprotein (LDL) cholesterol lead to depression?

Association Between Lowering LDL Cholesterol and Depression

There is no strong evidence that lowering LDL cholesterol leads to depression, and the cardiovascular benefits of LDL reduction outweigh any potential psychological risks, especially in high-risk patients. 1, 2

Evidence on LDL Reduction and Depression

The relationship between lowering LDL cholesterol and depression has been extensively studied with mixed but predominantly reassuring results:

• Recent guidelines: The European Heart Journal (2021) review on very low LDL levels (<30 mg/dL) indicates that while there were initial concerns about potential side effects, the majority of studies have demonstrated no significant association between very low LDL-C and major side effects, including depression 1.

• Conflicting research: While some older studies suggested a possible link between low cholesterol and depression:

  • A large 2020 NHANES cross-sectional study found no association between low cholesterol levels and increased risk of depression 3.
  • In fact, this study found that very low total cholesterol (<129 mg/dL) was associated with a decreased risk of depression (OR = 0.64,95% CI 0.42-0.98) 3.

• Older studies with limitations: Some earlier research suggested associations between low serum total cholesterol and depression or suicide 4, 5, but these studies had significant limitations including:

  • Inability to establish causality (low cholesterol might be a result of depression rather than a cause)
  • Lack of control for confounding factors
  • Small sample sizes in some studies

Cardiovascular Benefits vs. Potential Risks

The cardiovascular benefits of LDL reduction are well-established and substantial:

• Meta-analyses show a clear dose-dependent relative reduction in cardiovascular disease with LDL cholesterol lowering, with every 1.0 mmol/L reduction associated with a 20-25% reduction in CVD mortality and non-fatal myocardial infarction 1, 6.

• The 2021 European Heart Journal review confirms that cardiovascular benefit continues to increase with lowering LDL-C even when very low LDL-C is attained 1.

• Individuals with genetic conditions characterized by lifelong very low LDL-C (such as PCSK9 loss-of-function mutations) generally demonstrate good health and experience significantly fewer coronary events compared to control groups 1, 2.

Clinical Recommendations

When considering LDL reduction therapy:

1. Target appropriate LDL levels based on risk:

   • For very high-risk patients: LDL-C <55 mg/dL or <1.8 mmol/L 1, 2
   • For high-risk patients: LDL-C <70 mg/dL or <2.5 mmol/L 1
   • For moderate-risk patients: LDL-C <100 mg/dL or <3 mmol/L 1

2. Monitor patients on intensive lipid-lowering therapy for:

   • Neurocognitive symptoms
   • Liver function
   • Glucose metabolism
   • Hematuria
   • Psychological symptoms (though not strongly supported by evidence)

3. Consider the mechanism of LDL-C reduction: Increased LDL clearance (as with statins and PCSK9 inhibitors) appears safer than decreased lipoprotein production 1, 2.

Important Caveats

• In a small subgroup analysis from a 2013 study, among 22 participants with LDL cholesterol <70 mg/dL, the prevalence of clinically significant depressive symptoms was 31.8% compared with 12.1% in the remaining cohort (p=0.005) 7. However, this finding was from a very small sample and has not been consistently replicated in larger studies.

• Patients currently taking psychiatric medications may require closer monitoring when achieving very low LDL levels, as one study showed higher aggression scores in this specific subgroup 7.

• The risk-benefit ratio should always be considered, with cardiovascular benefits likely outweighing potential psychological risks, especially in patients with high cardiovascular risk 1, 2.

In conclusion, while monitoring for psychological symptoms is reasonable in patients achieving very low LDL levels, the current evidence does not support withholding appropriate lipid-lowering therapy due to concerns about depression.