Psychosomatics 44:412-414, October 2003
© 2003 The Academy of Psychosomatic Medicine
Behavioral Implications of Lowering Cholesterol Levels: A Double-Blind Pilot Study
Tom Ormiston, M.D.,
Owen M. Wolkowitz, M.D.,
Victor I. Reus, M.D., and
Francesca Manfredi, D.O.
Received Dec. 26, 2002; revision received Feb. 19, 2003; accepted March 12, 2003. From the Department of Internal Medicine, Santa Clara Valley Medical Center, San Jose, Calif.; and the Department of Psychiatry, UC, San Francisco, Medical Center, San Francisco. Address correspondence to Dr. Ormiston, Clinical Assistant Professor of Medicine, 751 S. Bascom Ave., San Jose, CA 95128-2699; Thomas.Ormiston{at}hhs.co.santa-clara.ca.us (e-mail).
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ABSTRACT
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The treatment of hypercholesterolemia may be associated with greater noncardiac mortality. This current pilot study sought to determine which behaviors, if any, are associated with decreases in cholesterol level. Twelve subjects received one of two cholesterol-reducing drugs or placebo. Cholesterol and behavioral ratings were measured at baseline, 4, and 52 weeks with standardized scales. Cholesterol levels markedly declined with concomitant significant increases in impulsivity ratings at 4 weeks. At 52 weeks, the increase in impulsivity ratings was no longer apparent, but depression ratings showed a significant improvement. This pilot study, although limited in size, raises the possibility that cholesterol-lowering drugs are associated with mild, time-limited increases in impulsivity and with mild, time-delayed improvements in depression ratings.
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INTRODUCTION
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The lowering of high serum cholesterol levels has been shown to decrease the incidence of morbidity and mortality due to coronary artery disease. Along with this benefit, however—some,1–4 but not all5—authors have noted a higher incidence of mortality due to murder, accidents, and suicide in subjects. This reputed increase more likely occurs early rather than late in treatment and does not seem to be linked to a particular dietary change or pharmacological agent. In support of a direct relationship between low cholesterol and adverse behavioral outcomes, prior studies have demonstrated a greater incidence of depression in women and elderly men with low cholesterol levels,6,7 an increase in the hostility and aggression levels of monkeys and humans with low cholesterol diets,4,8–10 and lower serum cholesterol levels among some patients with recent impulsive or violent suicidal attempts.11–13
Because cholesterol-lowering therapies continue to be widely prescribed, it is important to ascertain the risks of such intervention. Most prior studies of the behavioral effects of cholesterol-lowering treatments were limited in that they investigated only the severe endpoint of behavioral perturbation—suicide or homicide.14 The current study sought to determine which more subtle behaviors, if any, are associated with pharmacologically mediated decreases in serum cholesterol levels.
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METHOD
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This study was conducted at the UC, San Francisco, Medical Center Lipid Clinic with a subject population randomly assigned to one of two cholesterol-lowering drugs in a double-blind fashion or a placebo (atorvastatin 10–20 mg/day or lovastatin 20–40 mg/day or placebo). The UC, San Francisco Lipid Clinic was part of a larger national multicenter study. Twelve subjects, chosen randomly from the study pool, gave informed consent to participate in this study approved by the institutional review board, but the specific hypotheses of the study were not revealed. The subjects were four men and eight women, 33 to 80 years old (mean=55). Concurrent medications were not changed during the course of the study. Psychological variables were measured at baseline, 4 weeks, and 52 weeks by using the Beck Depression Inventory,15 the Buss-Durkee Hostility Inventory,16 and the Barrett Impulsivity Scale.17 Serum total cholesterol levels were measured the morning of each clinic visit after an overnight fast. Because of the small sample size, data were analyzed nonparametrically with the Wilcoxon signed rank test and Spearman's rank-order correlation.
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RESULTS
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The 12 subjects had severe hypercholesterolemia at baseline, and their serum total cholesterol levels were significantly lower within 4 weeks of treatment (baseline: mean=281 mg/dl, SD=39; week 4: mean=205 mg/dl, SD=33) (t=9.08, df=11, p<0.0001) (Figure 1). Once the treatment regimens were unblinded at the conclusion of the study (week 52), the participants at this site were found to have been randomly assigned to lovastatin (N=3), atorvastatin (N=9), and placebo (N=0). All of the patients had lowered their cholesterol levels, and their levels were combined for behavioral analysis, since the primary independent variable in this study was change in cholesterol level, irrespective of group assignment. Concomitant with this decrease in total cholesterol level at 4 weeks was a mild but significant increase in impulsivity, as measured by the Barrett Impulsivity Scale (baseline: mean=51.6, SD=6.2; week 4: mean=54.4, SD=6.8) (t=-1.88, df=11, p<0.05). Nine of 12 patients demonstrated this increase in impulsivity. The magnitude of the decrease in cholesterol levels was not significantly correlated with the magnitude of the increase in impulsivity ratings (rs=0.018, p<0.43). Ratings of depression and hostility did not significantly change by the 4-week point.
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FIGURE 1. Changes in Total Cholesterol Levels in 12 Subjects Given One of Two Cholesterol-Lowering Drugs Over 52 Weeks
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At week 52, total serum cholesterol levels remained significantly low (mean=199 mg/dl, SD=28) compared to baseline levels (t=8.31, df=11, p<0.0001). By week 52, mean impulsivity ratings had returned to near baseline (mean=52.4, SD=8.2) (t=-0.91, df=11, p=0.75). Hostility ratings did not change significantly compared to baseline. Depression ratings mildly but significantly improved by week 52 compared to baseline (baseline Beck Depression Inventory rating: mean=6.3, SD=5.1; week 52: mean=5.6, SD=6.3) (t=2.27, df=11, p<0.05). Eight of the 12 subjects showed a decrease in depression ratings. Because of the small sample size, it was not possible to ascertain if there was a gender difference.
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DISCUSSION
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In this double-blind pilot study, the subjects taking cholesterol-lowering drugs showed early (within 4 weeks) increases in ratings of impulsive behavior but time-delayed (as late as 1 year) improvements in ratings of depressive symptoms. This study was limited by its small group size, multiple behavioral measures, and lack of a placebo-control group; the drugs were administered in a double-blind fashion, with placebo assignment as one possibility, but all 12 subjects who participated in our study received active drug and had their cholesterol level pharmacologically reduced. Although we were unable to compare behavioral changes to a group that did not have their cholesterol levels lowered, each subject served as his or her own control subject. The interpretive difficulty posed by this unbalanced design was somewhat mitigated by our a priori interest in analyzing changes in behavior in relation to changes in cholesterol levels, regardless of the method of cholesterol lowering.
Our results demonstrated a modest increase in impulsivity after a short course of cholesterol-lowering therapy that dissipated over a longer course of therapy, suggesting that this behavioral effect may occur early in treatment and be transitory. This finding was previously suggested by the findings of Lindberg et al.2 and Davidson et al.18 Furthermore, Garland et al.13 showed significant negative correlations between serum cholesterol levels and self-reported scores of impulsivity in parasuicidal patients.
Consistent with prior research,19,20 no change in hostility levels was observed at either 4 or 52 weeks in our subjects. There was, however, evidence of a mild improvement in the patients' self-rated depression score at 52 weeks but not at 4 weeks. Our subjects were not clinically depressed at baseline, however, and it is unknown if similar findings would be seen in patients with major depressive disorder. Glueck et al.21 found that pharmacological and dietary treatment of hypertriglyceridemia was associated with a significant amelioration of depressive symptoms at 30 and 54 weeks. They suggested that the apparent antidepressant effects were possibly due to improved cerebral perfusion and oxygenation.21
Individual risk factors for experiencing behavioral change with cholesterol-lowering drug treatments are unknown. The rare individuals in previous studies who committed suicide or were involved in homicide or serious accidents concomitant with a decrease in their cholesterol levels may, for as yet unknown reasons, have been more susceptible to the effects of cholesterol lowering.1 Possible mechanisms of such effects, such as changes in steroid metabolites of cholesterol,22 changes in cell membrane composition,22 and decreases in brain serotonin activity,23,24 have been postulated to contribute to such effects. It is theoretically possible that there could be a tangible behavioral perturbation with profound changes in cholesterol levels that would return to normal over time as the body reestablishes homeostasis to the new serum cholesterol level. In order to better investigate the possibility of common, albeit subtle, behavioral perturbations, future large-scale cholesterol-lowering studies should include measuring impulsivity and depressive symptoms to assess behavior at both acute and long-term time points.
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ACKNOWLEDGMENTS
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The authors thank Dr. John Kane and Dr. Mary Malloy of the UC, San Francisco Lipid Clinic for their help. The views expressed in this article, however, are solely those of the authors.
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REFERENCES
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ABSTRACT
INTRODUCTION
