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Cholesterol, mood, and vascular health: Untangling the relationship

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Does low cholesterol predispose to depression and suicide, or vice versa?



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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 the 2 primary causes of excess deaths in patients with mood disorders: suicide and vascular disease.1

Examining excess mortality in patients with mood disorders Dr. Jess G. Fiedorowicz discusses the two primary causes of excess deaths in patients with mood disorders: suicide and vascular disease.

Plausible links

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.8

Depression. Several studies have shown an association between low cholesterol and depressive symptoms, although this finding has not been replicated in Asian subjects.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 patients receive pharmacotherapy for major depressive symptoms.13 These findings have led to speculation that low serum cholesterol in patients with mood disorders is partially 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 found statistically significant correlations between low cholesterol and future or past suicidal behavior; however, low cholesterol explained <0.01% of suicidal behavior.15 Studies comparing cholesterol levels of individuals following violent vs nonviolent suicide attempts have demonstrated stronger associations.15

Assessing suicide risk. Current evidence does not support considering low serum cholesterol a risk factor for suicide. One study 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.

Box 1

Neurobiologic implications of low 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 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

a. Vevera J, Fisar Z, Kvasnicka T, et al. Cholesterol-lowering therapy evokes time-limited changes in serotonergic transmission. Psychiatry Res. 2005;133(2-3):197-203.
b. Kaplan JR, Shively CA, Fontenot MB, et al. Demonstration of an association among dietary cholesterol, central serotonergic activity, and social behavior in monkeys. Psychosom Med. 1994;56(6):479-484.
c. Chattopadhyay A, Paila YD. Lipid-protein interactions, regulation and dysfunction of brain cholesterol. Biochem Biophys Res Commun. 2007;354(3):627-633.
d. Singh P, Paila YD, Chattopadhyay A. Differential effects of cholesterol and 7-dehydrocholesterol on the ligand binding activity of the hippocampal serotonin(1A) receptor: implications in SLOS. Biochem Biophys Res Commun. 2007;358(2):495-499.
e. Sjögren B, Hamblin MW, Svenningsson P. Cholesterol depletion reduces serotonin binding and signaling via human 5-HT(7(a)) receptors. Eur J Pharmacol. 2006;552(1-3):1-10.
f. Scanlon SM, Williams DC, Schloss P. Membrane cholesterol modulates serotonin transporter activity. Biochemistry. 2001;40(35):10507-10513.
g. Vevera J, Fisar Z, Kvasnicka T, et al. Cholesterol-lowering therapy evokes time-limited changes in serotonergic transmission. Psychiatry Res. 2005;133(2-3):197-203.
h. Sooksawate T, Simmonds MA. Effects of membrane cholesterol on the sensitivity of the GABA(A) receptor to GABA in acutely dissociated rat hippocampal neurones. Neuropharmacology. 2001;40(2):178-184.
i. Abulrob A, Tauskela JS, Mealing G, et al. Protection by cholesterol-extracting cyclodextrins: a role for N-methyl-daspartate receptor redistribution. J Neurochem. 2005;92(6):1477-1486.
j. Huang P, Xu W, Yoon SI, et al. Cholesterol reduction by methyl-beta-cyclodextrin attenuates the delta opioid receptor-mediated signaling in neuronal cells but enhances it in non-neuronal cells. Biochem Pharmacol. 2007;73(4):534-549.
k. Butchbach ME, Tian G, Guo H, et al. Association of excitatory amino acid transporters, especially EAAT2, with cholesterol-rich lipid raft microdomains: importance for excitatory amino acid transporter localization and function. J Biol Chem. 2004;279(33):34388-34396.
l. Fawcett J, Busch KA, Jacobs D, et al. Suicide: a four-pathway clinical-biochemical model. Annals N Y Acad Sci. 1997;836:288-301.
m. Garland M, Hickey D, Corvin A, et al. Total serum cholesterol in relation to psychological correlates in parasuicide. Br J Psychiatry. 2000;177:77-83.
n. Ormiston T, Wolkowitz OM, Reus VI, et al. Behavioral implications of lowering cholesterol levels: a double-blind pilot study. Psychosomatics. 2003;44(5):412-414.
o. Golomb BA. Cholesterol and violence: is there a connection? Ann Intern Med. 1998;128(6):478-487.

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