In the early 1990s several studies suggested a link between low cholesterol (< 160 mg/dL) and unnatural deaths, including suicide.2-4 Follow-up studies confirmed associations between low cholesterol and suicide attempts, especially violent ones.5 These associations are compelling given the neurobiologic effects of cholesterol, such as a net reduction of serotonergic function (Box 1). Low cholesterol 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.
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 receptorsd,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-aminobutyric acid receptors,hN-methyl-D-aspartate receptors,i opioid signaling,j and excitatory amino acids transport.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 temporary,n which is similar 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, including suicide.o
Multiple randomized controlled trials have not shown increased depression and suicide with use of lipid-lowering agents in healthy populations
Closely monitor individuals with mood disorders for changes in behavior or mental status after starting a lipid-lowering agent
Cholesterol, mood, and vascular health: Untangling the relationship
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