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Cholesterol and Mood: What’s the Link?

Cholesterol and Mood: What’s the Link?

[The following is a transcript of a podcast by Dr James Lake.]

It has long been observed that total cholesterol levels are consistently lower in more severely depressed and more aggressive patients. Because of these findings, it has been suggested that total cholesterol might be a clinically useful biological marker for detecting the risk of suicide and that it may be of prognostic value in managing severely depressed patients.

A national campaign to lower serum cholesterol levels began in the mid-80s when accumulating evidence showed convincingly that cholesterol lowering reduces the risk of heart attacks and cardiovascular disease. Since then, there have been increasing concerns about the effects of cholesterol-lowering interventions on overall mortality. Although recent research findings have helped to clarify these relationships, there are still many unanswered questions.

The relationship between serum cholesterol and mood is complex and research findings to date are inconsistent. Research findings going back to the early 90s show that serum cholesterol - especially the HDL fraction - is significantly lower in many patients with major depressive disorder than in non-depressed individuals, and that clinical improvement following antidepressant therapy is often associated with a significant increase in serum total cholesterol [1-4]. A review of 6 randomized trials dating from the 1980s through the early 1990s found that while lowering abnormally high serum cholesterol levels (below 150 mg/dL) decreased the number of deaths from coronary heart disease, cholesterol lowering was actually associated with increased mortality due to suicide or violence [5].

Even though more recent studies [6,7] have failed to replicate these early findings, an alarming trend is emerging. Although it has been established that lowering cholesterol levels reduces morbidity and mortality from heart disease, recent research findings suggest that widely used cholesterol lowering medications - the statins - may fail to improve overall survival because of an associated increased risk in non-cardiovascular mortality, including especially suicide and violence-related deaths. For example, the findings of a large case-control study published in 2004 suggest that changes in total serum cholesterol levels following treatment with statins are inversely related to severity of depressed mood [8]. Non-suicidal depressives tend to have cholesterol levels in the range of 180 mg/dL, and severely depressed suicidal patients tend to have serum total cholesterol levels in the range of 150 mg/dL or lower.

Many hypotheses have been advanced in efforts to explain the relationship between cholesterol and depressed mood. Until very recently, however, research has failed to provide clear answers. Several studies have found that low serum lipid levels are associated with persistently low platelet serotonin levels in depressed suicidal patients [9,10]. It has been hypothesized that low cholesterol levels indirectly lead to reduced brain serotonin because of the requirement of adequate cholesterol in nerve cell membranes to maintain the functional integrity of serotonin receptors [9,11]. These observations are consistent with a high rate of severe depression and suicide attempts in individuals afflicted with a rare genetic syndrome that causes an enzyme deficiency resulting in abnormal low serum cholesterol [12].

However, this hypothesis is not clearly supported by findings of human clinical trials.  For example, a review of controlled studies on the effects of statins on mental health published in 2006 [13] found no statistically significant effect of low serum cholesterol concentrations on psychological well being. In fact, the reviewers noted that many randomized controlled trials actually found reductions in symptoms of depressed mood, anxiety and hostility in patients treated with statins. However, further analysis of pooled data from these studies revealed an interesting finding—in contrast to all other cholesterol-lowering drugs—only the lipophilic statins—were associated with significant worsening of depressed mood, increased hostility, and increased suicide risk.

Lovastatin and simvastatin are the most lipophilic agents; these are followed by atorvastatin, fluvastatin, and rosuvastatin, and finally pravastatin. The reported incidence of serious adverse effects in general is higher for the more lipophilic statins (eg, lovastatin (Mevacor, Altocor, Altoprev) and simvastatin (Zocor and Lipex) than the other statins. Of note, the lipophilic agents cross the blood-brain barrier more readily, and are more frequently associated with reports of impaired cognitive functioning and insomnia.

Pazarlis and colleagues postulated that lipophilic statins may cause deleterious effects on mental health through an immunomodulatory mechanism [13]. In contrast to non-lipophilic statins, the more lipophilic statins readily penetrate the blood-brain-barrier where they inhibit HMG-CoA reductase, suppress several cytokines (including interferon-gamma, and interleukins IL-2 and IL-12), which results in lowering of tryptophan availability in the brain and decreased serotonin synthesis. 

Adding to these findings, a very important study published only in the past few months is helping to put earlier research findings into a more coherent theoretical framework. This work has led to a novel theory that directly links abnormal low brain cholesterol levels to impaired serotonin function. The new theory also helps explain the apparent correlation between increased rates of suicide and violent behavior and low cholesterol levels in individuals taking certain kinds of cholesterol lowering drugs.

In this study published in the journal Biochemistry in June of this year, Shrivastava and colleagues [14] examined the effect of chronic cholesterol depletion induced by the cholesterol-lowering drug mevastatin on the function of human serotonin 1A receptors expressed in hamster ovary cells. They reported a significant reduction in the level of serotonin binding and G-protein coupling to serotonin 1A receptors resulting from chronic cholesterol depletion following treatment with mevastatin, which is one of the more lipophilic statins.

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