Cholesterol, mood, and vascular health: Untangling the relationship

A growing body of literature examining the putative links among cholesterol, mood disorders, and suicide has produced inconsistent findings and unclear clinical implications that may leave psychiatrists unsure of how to interpret the data. Understanding cholesterol’s role in mood disorders may be relevant to 2 causes of excess deaths in this population: suicide and vascular disease, which account for most of the excess deaths observed in those with mood disorders.¹

A possible link

In the early 1990s several studies suggested a link between low cholesterol and unnatural deaths, including suicide.^2–4 Follow-up studies confirmed associations between low cholesterol and suicide attempts, especially violent ones.⁵ These associations were compelling given the known neurobiologic effects of cholesterol, such as a net reduction of serotonergic function (Box 1). Low cholesterol concentrations may predispose an individual to aggression, impulsivity, and violence (Table 1).⁶ Many studies have found that patients with mood disorders have lower cholesterol levels;⁷ however, other research suggests they are at increased risk of hyperlipidemia, typically hypertriglyceridemia rather than hypercholesterolemia.⁸

Box 1. Neurobiology of cholesterol.

The neurobiologic effects of low cholesterol—particularly those related to serotonergic hypofunction—are thought to be mediate impulsive, aggressive, and violent behaviors that may predispose an individual to suicide.^a,b The CNS contains one-fourth of the body’s free cholesterol, ^c which is synthesized primarily in situ.

Cholesterol improves membrane stability, reduces permeability, and may influence serotonergic function. Cholesterol depletion may impair function of 5-HT1A and 5-HT7 receptors^d,e and serotonin transporter activity.^f Reduced cholesterol after treatment with simvastatin—an HMG-CoA reductase inhibitor that readily crosses the blood-brain barrier—resulted in acute (1-month) increases in serotonin transporter activity followed by subacute (>2 months) decreases.^g Lower cholesterol levels may further decrease expression of serotonin receptors and cause a net reduction in serotonergic activity.

In addition, cholesterol is necessary for synapse formation and myelin production. Cholesterol depletion may have more diffuse effects on neurotransmission, such as gamma-aminobutryic acid receptors,^h N-methyl-D-aspartate receptors,ⁱ opioid signaling,^j and transport of excitatory amino acids.^k

Impulsivity associated with low serotonergic function and low total cholesterol has been suggested as a potential pathway for suicide.^l Low cholesterol is associated with self-report measures of impulsivity;^m however, increased impulsivity associated with lipid-lowering therapy may be temporaryⁿ akin to the time-limited changes in serotonin transporter activity.^g Human and animal data have suggested that low cholesterol may be linked to violent behaviors, which may include suicide.^p

Table 1.

Psychiatric symptoms, syndromes, and behaviors associated with low cholesterol^*

Symptoms	Anxiety, depressed mood, emotional lability, euphoria, impulsivity, irritability, suicidal ideation, aggression
Syndromes	Anorexia nervosa, bipolar disorder, borderline personality disorder, major depressive disorder, seasonal affective disorder
Behaviors	Suicide and suicide attempts, violence

^*Additional, small studies have suggested possible relationships with dissociative and panic disorders

Depression

Several studies have shown an association between low cholesterol and depressive symptoms, although this finding has not been replicated in Asian samples.^9,10 Patients with manic or mixed syndromes have been found to have lower serum cholesterol,¹¹ and individuals with major depression and bipolar disorder have lower cholesterol levels in the brain compared with healthy controls.¹² Some studies have observed higher total cholesterol levels after pharmacotherapy of major depressive symptoms.¹³ These findings have led to speculation that low serum cholesterol in patients with mood disorders in part is a state-dependent effect of depressive illness.

Suicide

Cohort, case-control, and cross-sectional studies have linked low cholesterol to an increased risk of suicide.^2,5 Individuals who attempt suicide by violent means have lower cholesterol compared with those who use less violent methods.^5,14 A meta-analysis has found statistically significant correlations between low cholesterol and future or past suicidal behavior; however, low cholesterol explained less than 0.01% of suicidal behavior.¹⁵ Studies comparing cholesterol levels of individuals following violent vs non-violent suicide attempts have demonstrated stronger associations.¹⁵

Assessing suicide risk

Current evidence does not support considering serum cholesterol as a risk factor when assessing suicide risk. One study has used cholesterol as a clinical predictor of suicide,¹⁶ but this model has not been prospectively validated. As a whole, the evidence does not suggest that cholesterol levels explain a substantial portion of suicidal behaviors.

Effects of lipid-lowering agents

If there is a causal relationship between low cholesterol and mood disorders, then it stands to reason that using cholesterol-lowering drugs should increase the risk of depression and suicide. However, the data do not support that conclusion.

Many case reports have documented adverse psychiatric reactions to statins, including depression, suicidality, emotional lability, agitation, irritability, anxiety, panic, and euphoria.¹⁷ In an early analysis of primary prevention trials, patients receiving cholesterol-lowering treatment—mainly non-statins—were estimated to have twice the risk of death by suicide or violence compared with controls.³ However, a more recent meta-analysis of larger clinical trials of lipid-lowering agents including statins and observational studies did not reveal an association between lipid-lowering medications and suicide.^15,18

In a large case-control study, statin users had a lower risk of depression (adjusted odds ratio [OR] 0.4, 95% confidence interval [CI]: 0.2 to 0.9) than patients taking non-statin lipid-lowering drugs (adjusted OR 1.0, 95% CI: 0.5 to 2.1).¹⁹ However, statins reduced cholesterol more (30% to 50%) than non-statin drugs (10% to 20%). A clinical trial of >1,000 patients with stable coronary artery disease treated with pravastatin—an HMG-CoA reductase inhibitor with low lipophilicity that is less likely to cross the blood-brain barrier—revealed no changes in self-reported anger, impulsiveness, anxiety, or depression.²⁰

This study did not exclude patients with psychiatric illness—who are at greatest risk of suicide—but other trials of lipid-lowering drugs did.²¹ As a result, the effects of lipid-lowering medications on psychiatric patients are unclear. A clinical trial is underway to assess the effects of pravastatin (low lipophilicity), simvastatin (high lipophilicity), or placebo on mood, sleep, and aggression.²¹

Which comes first?

Much of the research linking low cholesterol, mood disorders, and suicidality could be confounded by depressed mood leading to reduced serum cholesterol. There has been considerable debate about whether low cholesterol predisposes patients to suicide or if depression independently leads to poor nutrition and therefore low cholesterol and increased suicide risk.^6,22

Some researchers have suggested that depression lowers cholesterol and increases risk of suicide,²³ but study designs have limited the ability to discern the directionality of the relationship. Attempts to control for depression-related malnutrition and weight loss—which lowers total cholesterol, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C)²⁴—suggest the association may be independent of these variables.^25–27 These findings suggest that cholesterol may be considered a trait marker and is not entirely state-dependent. However, multiple large, long-term randomized controlled trials have not shown increased depression and suicide with use of lipid-lowering agents in healthy populations.²⁰

The Figure illustrates the known epidemiologic associations of low cholesterol, low serotoninergic function, and suicide and contrasts conceptual models of cholesterol as state and trait markers. A case can be made for cholesterol as both a state and trait marker, and these models could overlap, with depression-induced decreases in cholesterol further mediating changes in serotonergic function and related behavioral sequelae.

Figure. Cholesterol, depression, and suicide: How are they linked?

Low cholesterol may be considered as a trait marker, predisposing patient to lower serotonergic function and placing them at greater risk for impulsivity, depression, aggression, and suicide. Other models suggest the associations are epiphenomenon, a state-dependent consequence of depression, and not part of a causal chain toward suicide.

Improving cardiac health

Limited epidemiologic studies suggest that patients with mood disorders may have lower levels of total cholesterol and LDL-C, but higher rates of hypertriglyceridemia compared with the general population.⁸ Unfortunately, psychiatric patients—who may be at increased risk of developing cardiovascular disease—may be less likely to be screened and appropriately treated for lipid abnormalities. To address this disparity, consider assuming an active role in assessing and managing hyperlipidemia in your patients with mood disorders. Be aware of your patients’ lipid profile and ensure that they follow monitoring recommendations.

The National Cholesterol Education Program recommends screening all adults age >20 for hyperlipidemia every 5 years using measures of total cholesterol, LDL-C, HDL-C, and triglycerides. If LDL-C or triglycerides exceed target values (Table 2), appropriate management includes recommending lifestyle changes and pharmacotherapy (Box 2). Patients should receive a fasting lipid profile before and 12 weeks after starting any antipsychotic²⁸ and semiannually thereafter.²⁹ Consider closely monitoring lipids when patients gain weight with any psychotropic. Refer patients with hyperlipidemia should be referred to a primary care physician, but can be managed by a mental health care provider if necessary.³⁰

Table 2.

National Cholesterol Education Program recommended target LDL levels

Risk category*	LDL goal	When to consider medications
CHD or CHD equivalent	<100 mg/dL	≥130 mg/dL
≥2 major risk factors	<130 mg/dL	≥130 to 160 mg/dL (based on 10-year risk)
0 or 1 risk factor	<160 mg/dL	≥190 mg/dL

CHD: coronary heart disease; HDL: high-density lipoprotein; LDL: low-density lipoprotein

^*Risk category is based on the presence of CHD or equivalent and major risk factors for CHD. CHD equivalents include symptomatic carotid artery disease, peripheral artery disease, and abdominal aortic aneurysm. Major risk factors include smoking, hypertension, low HDL, family history, and age. LDL levels to consider medications for those with ≥2 major risk factors vary by 10-year CHD risk

Source: National Cholesterol Education Program, Adult Treatment Panel III (ATP III) Quick Desk Reference. Available at: www.nhlbi.nih.gov/guidelines/cholesterol/atglance.htm.

Box 2. Recommendations for treating hyperlipidemia.

Current guidelines state that when a patient’s low-density lipoprotein cholesterol (LDL-C) exceeds targets (Table 2), first recommend lifestyle changes such as a diet low in saturated fat (<7% of calories) and cholesterol (<200 mg/d), weight management, and exercise. Increases in soluble fiber (10 to 25 g/d) and plant stanols/sterols also may be considered. If LDL-C levels are still too high, pharmacologic therapy such as an HmG-CoA reductase inhibitor is suggested.

Treatment of elevated triglycerides (≥150 mg/dL) includes reaching the target LDL-C, intensifying a weight management program, and increasing exercise. Smoking cessation and limiting alcohol can be addressed when indicated. If triglyceride levels are ≥200 mg/dL after the LDL-C target is reached, set a secondary goal of reaching a target non-high-density lipoprotein cholesterol (non-HDL-C) (total cholesterol minus HDL-C) 30 mg/dL greater than the LDL goal. This can be achieved by adding an LDL-lowering drug such as a statin, nicotinic acid, or ezetimibe. When triglycerides are ≥500 mg/dL, more aggressive intervention such as with a fibrate, omega-3 fatty acids, very low-fat diets, and exercise is required to prevent pancreatitis.

Closely monitor individuals with mood disorders for any changes in behavior or mental status after starting a lipid-lowering agent and consider discontinuing the drug if a patient develops an adverse reaction. If symptoms return after medication rechallenge, consider other management strategies such as an alternative lipid-lowering agent or re-emphasis of behavioral measures.

Bottom Line

Low cholesterol has been associated with suicide, but not strongly or consistently enough to warrant routine use in suicide risk assessment. Lipid-lowering therapies do not appear to increase overall suicide risk. Patients with mood disorders are at higher risk of developing cardiovascular disease and should not be deprived of potentially life saving, lipid-lowering treatment, although close monitoring for adverse effects is warranted.

Related Resources

• Fiedorowicz JG, Coryell WH. Cholesterol and suicide attempts: a prospective study of depressed inpatients. Psychiatry Res. 2007;152(1):11–20.

• National Cholesterol Education Program, Adult Treatment Panel III (ATP III) Quick Desk Reference. www.nhlbi.nih.gov/guidelines/cholesterol/atglance.htm.

• Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA. 2001;285(19):2486–2497.

Drug Brand Names

Pravastatin * Pravachol

Simvastatin * Zocor

Ezetimibe * Zetia