Are Cholesterol Levels Linked to Bipolar Disorder?

Sarah T. Melton, PharmD


May 16, 2011


What is the significance of cholesterol levels in patients with bipolar disorder? Do low cholesterol levels contribute to the morbidity of the disease?

Response from Sarah T. Melton, PharmD
Director of Addiction Outreach; Associate Professor of Pharmacy Practice, Appalachian College of Pharmacy, Oakwood, Virginia; Clinical Pharmacist, C-Health, PC, Lebanon, Virginia

Bipolar disorder, a chronic, relapsing brain disorder, usually develops in the late teens or early adult years, with half of all cases starting before age 25. Patients with bipolar disorder often have extremes of mania and depression that alternate with periods of normal mood. During manic episodes, behavioral changes such as restlessness, insomnia, irritability, risk-taking, or thoughtless behavior will occur. During the depressive phase, patients often become lethargic, lose interest in activities they previously enjoyed, and are at risk for suicidal behavior.[1]

Psychiatric symptoms have been associated with low cholesterol and include anxiety, depression, euphoria, irritability, aggression, and suicidal ideation.[2] A link between cholesterol and mood disorders has been investigated.

Cholesterol is abundant in the brain and is important in many aspects of cellular structure and function. Cholesterol affects the fluidity of cell membranes, membrane permeability, exchange processes, and may influence serotonergic function.[3] Cholesterol depletion may impair function of 5-HT1A and 5-HT7 receptors and serotonin receptor activity.[2,3] Over time, lower cholesterol levels may further decrease expression of serotonin receptors and cause a reduction in serotonergic activity. A correlation between low levels of 5-hydroxyindoleacetic acid in cerebrospinal fluid and cholesterol has been shown in suicide attempters.[4]

More than 30 studies have linked low cholesterol with suicidal behavior.[5] Other studies have shown a possible link between low cholesterol levels and increased number of suicides, suicide attempts, and self-injurious behavior; these findings have not been consistently replicated, particularly in the Asian population.[4] Overall evidence does not support routinely using cholesterol levels in assessing suicide risk. In addition, research linking low cholesterol with suicide may be confounded by depressed mood leading to lower serum cholesterol as a result of poor nutrition.[2]

Compared with controls, patients with bipolar disorder (mania and mixed syndromes) had significantly lower total serum cholesterol.[6,7] Patients with bipolar and major depressive disorders had lower cholesterol levels in the brain compared with healthy controls.[8] In one study, patients with bipolar disorder in remission had lower cholesterol concentrations compared with controls.[9]

Other studies have shown an increased prevalence of hyperlipidemia, primarily in the form of hypertriglyceridemia.[2] Treatment of mania appeared to reduce cholesterol in one study[6] but increase it in another.[10] A cohort trial in 131 participants examined the relationship between fasting total cholesterol and subsequent depressive and manic symptoms.[11] Among bipolar patients (n=65), low cholesterol predicted a higher proportion of follow-up weeks with manic but not depressive symptoms.

Following the hypothesis that lower cholesterol levels may be associated with mood disorders, it is reasonable to ask if cholesterol-lowering medications are associated with increased depression and suicidal ideation. A review of the literature[12] found many case reports of adverse psychiatric effects associated with the use of statins, fibrates, and ezetimibe. A meta-analysis of large clinical trials of lipid-lowering agents did not show an association between use of these medications and rates of suicide.[5]

Statin medications with low lipophilicity (eg, pravastatin) are less likely to cross the blood-brain barrier and therefore may be less likely to cause cognitive or psychiatric adverse effects. The University of California, San Diego Statin Study is a double-blind, placebo-controlled study assessing outcomes pertaining to cognition, behavior, and quality of life in patients prescribed pravastatin 40 mg, simvastatin 20 mg, or placebo.[13] This ongoing study will, we hope, clarify the noncardiac effects of statins, particularly the effects of low or lowered cholesterol on cognitive function, aggression, and serotonin biochemistry.

To further complicate analysis of the role of cholesterol in bipolar disorder, epidemiologic studies show that the rate of metabolic syndrome in patients with bipolar disorder is increased relative to the general population.[14] This is seen internationally and is associated with more complex illness, less favorable response to treatment, and poor outcomes.[14] One study found that bipolar patients who met criteria for metabolic syndrome were more likely to report a lifetime history of suicide attempts.[15] The association between metabolic syndrome and bipolar disorder is mediated by both iatrogenic and noniatrogenic factors.[14,15]

Patients with bipolar disorder should be screened for risk factors for metabolic syndrome before treatment. Second-generation antipsychotics (SGAs) are commonly used in the treatment of bipolar disorder and are associated with causing or worsening metabolic syndrome. Therefore, healthcare professionals should perform the following in patients with bipolar disorder requiring SGAs[16]:

  • Obtain body mass index, personal/family history, waist circumference at baseline;

  • Obtain fasting plasma glucose, fasting lipid panel, and blood pressure at baseline;

  • Reassess weight change at 4, 8, and 12 weeks after initiation or change in antipsychotic therapy and quarterly thereafter; and

  • Reassess fasting plasma glucose, lipids, and blood pressure at 3 months and annually thereafter or more often in those with a higher baseline risk for diabetes or hypertension.

The literature supports a relationship between cholesterol levels and affective symptoms in patients with mood disorders, including bipolar disorder. However, the findings are inconsistent and suggest that the relationship between mood, cholesterol levels, and neurotransmitter function is very complex. Lower cholesterol levels are associated with increased risk for suicide and future manic symptomatology. However, bipolar patients are also at risk for metabolic abnormalities including obesity, diabetes, and hyperlipidemia, which affect clinical presentation, course, and response to treatment. Patients should be carefully monitored during treatment because many medications used to treat bipolar disorder can worsen metabolic abnormalities. More studies are needed to clearly identify the correlation of cholesterol levels with mood, risk for suicide, and the biochemistry of serotonin.


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