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.

These findings show that low nerve cell membrane cholesterol directly results in a decrease in the number of serotonin receptors, resulting in an overall reduction of serotonergic transmission in the brain. Significantly, the researchers also showed that the effect of chronic cholesterol depletion on serotonin receptor binding resulting from statin use is completely reversible when the drug is discontinued.

A study published in the July, 2010 issue of Biological Psychiatry reports important new findings that help to further elucidate relationships between cholesterol, severity of depressed mood, and serotonin receptor dysfunction [15]. In this large longitudinal study 1040 women and 752 men aged 65 and older were followed over a 7-year period. A standardized rating scale was used to rate the “level” of depressed mood at baseline, and at 2, 4, and 7 years. Serum lipid levels, apolipoprotein E, and serotonin transporter related genes were evaluated at baseline. The researchers identified a consistent gender-specific relationship between severity of depressed mood and serum levels of specific cholesterol fractions. Women with low levels of HDL (the “good” cholesterol fraction of cholesterol) who were therefore at greater risk for coronary artery disease were also more likely to have severe symptoms of depressed mood. In contrast, more depressed men were more likely to have low levels of LDL (the “bad” fraction), and were therefore at lower risk of coronary artery disease. These clinical differences in vulnerability to depressed mood were consistent with the finding of a significant relationship between low LDL cholesterol and dysfunction of the serotonin transporter gene in men, but not in women. The authors concluded that late-onset depressed mood may have a “complex gender-specific etiology” involving genetic vulnerability in a population of men at highest risk.

It is important to note that different mechanisms related to cholesterol that increase susceptibility to depressed mood are not mutually exclusive. All of these mechanisms probably contribute to the complex relationship between cholesterol and mental health depending on abnormalities of specific cholesterol fractions, gender, and genetic predispositions. In this broad context of multiple environmental and genetic factors, potentially harmful effects of lipophilic statins may be mediated by both indirect immunomodulatory effects and direct effects at the level of G-protein coupling involving serotonin receptors.  

The Take-Home Lessons
More than 2 decades of clinical research findings have now been backed up by basic research pointing to discrete immunological and cellular mechanisms through which reduced brain cholesterol levels related to statin use indirectly or directly interfere with normal serotonin receptor functioning and normal brain serotonin activity levels. While large prospective human clinical trials are needed to replicate these findings, it is prudent to check cholesterol levels of severely depressed patients, especially those who are non-responsive or only partially responsive to antidepressants, to make appropriate dietary recommendations for reducing fatty foods, and to address mental health issues that may be related to the use of certain cholesterol lowering drugs. Finally, suicide precautions should be undertaken when managing any severely depressed patient with a serum total cholesterol level of 150 mg/dL or lower.

Several common-sense changes in diet and lifestyle can significantly reduce total cholesterol and help our depressed patients achieve a healthier balance between “good” and “bad” cholesterol:

• Keep it low-but not too low. Advise your depressed patients who are being treated for elevated cholesterol levels to work their primary physician or cardiologist to regulate their total serum cholesterol levels not significantly lower than 160 mg/dL, and to preferentially avoid the more lipophilic statins (eg, lovastatin [Mevacor, Altocor, Altoprev] and simvastatin [Zocor and Lipex] while using non-statin cholesterol-lowering drugs or statins that are less lipophilic (eg, rosuvastatin [Crestor and Pravachol].)

• Exercise more. Exercise is known to increase HDL while lowering LDL levels.

• Stop smoking. Cigarettes lower HDL and raise LDL levels.

• Avoid processed foods. Prepared foods with trans-fats raise LDL and lower HDL.

• Follow a Mediterranean diet. Monounsaturated fats (eg, olive oil and avocadoes) increase HDL and lower LDL.

• Eat foods that contain omega-3s. Fatty fish like sardines and salmon contain omega-3 fats that raise HDL and lower LDL.

• Eat more whole grains. Whole grains contain dietary fiber and niacin, both of which raise HDL and lower LDL.

References:

1. Olusi SO, Fido AA. Serum lipid concentrations in patients with major depressive disorder. Biol Psychiatry. 1996;40:1128-1131.
2. Maes M, Smith R, Christophe A, Vandoolaeghe E, et al. Lower serum high-density lipoprotein cholesterol (HDL-C) in major depression and in depressed men with serious suicidal attempts: relationship with immune-inflammatory markers. Acta Psychiatr Scand. 1997;95:212-221.
3. Sarchiapone M, Roy A, Camardese G, De Risio S. Further evidence for low serum cholesterol and suicidal behaviour. J Affect Disord. 2000;61:69-71.
4. Gabriel A. Changes in plasma cholesterol in mood disorder patients: does treatment make a difference? J Affect Disord. 2007;99:273-278. Epub 2006 Sep 18.
5. Muldoon MF, Manuck SB, Matthews KA. Lowering cholesterol concentrations and mortality: a quantitative review of primary prevention trials. BMJ. 1990;11;301:309-314.
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7. Deisenhammer EA, Kramer-Reinstadler K, Liensberger D, et al. No evidence for an association between serum cholesterol and the course of depression and suicidality. Psychiatry Res. 2004;121:253-261.
8. Kim C, Beckles GL. Cardiovascular disease risk reduction in the Behavioral Risk Factor Surveillance System. Am J Prev Med. 2004;27:1-7.
9.  Steegmans PH, Fekkes D, Hoes AW, et al. Low serum cholesterol concentration and serotonin metabolism in men. BMJ. 1996;312:221.
10. Alvarez JC, Cremniter D, Lesieur P, et al. Low blood cholesterol and low platelet serotonin levels in violent suicide attempters. Biol Psychiatry. 1999;45:1066-1069.
11. Sarchiapone M, Camardese G, Roy A, et al. Cholesterol and serotonin indices in depressed and suicidal patients. J Affect Disord. 2001;62:217-219.
12. Lalovic A, Sequeira A, DeGuzman R, Chawky N, et al. Investigation of completed suicide and genes involved in cholesterol metabolism. J Affect Disord. 2004;79:25-32.
13. Pazarlis P, Katsigiannopoulos K, Bimolou S, et al. Poster presentation. Statins, cholesterol lowering and mental health: a review. Ann General Psychiatry. 2006,5(suppl 1):S251. http://www.biomedcentral.com/content/pdf/1744-859X-5-S1-S251.pdf14. Shrivastava S, Pucadyil TJ, Paila YD, et al. Chronic cholesterol depletion using statin impairs the function and dynamics of human serotonin(1A) receptors. Biochemistry. 2010; 49:5426-5435.
15. Marie-Laure Ancelin, Isabelle Carrière, Jean-Philippe Boulenger, et al. Gender and genotype modulation of the association between lipid levels and depressive symptomatology in community-dwelling elderly (The ESPRIT Study). Biological Psychiatry. 2010;68(2):125-132. http://www.biologicalpsychiatryjournal.com/article/S0006-3223(10)00393-8/abstract