Simvastatin Causes Changes in Affective Processes in Elderly Volunteers

Knashawn Morales, ScD; Marsha Wittink, MD; Catherine Datto, MD; Suzanne DiFilippo, RN; Mark Cary, PhD; Thomas TenHave, PhD; Ira R. Katz, MD, PhD


J Am Geriatr Soc. 2006;54(1):70-76. 

In This Article


The results reported here confirm the hypothesis that simvastatin administration can lead to adverse effects on affect and affective processes. The effects include a time-dependent decrease in positive affect and a transient effect on the effect of negative events on negative affect. The latter effects correspond to an initial increase in the subjects' sensitivity to the negative events or hassles of everyday life that is then attenuated over the course of a number of weeks.

Although it is statistically significant, the decrease in positive affect over time due to simvastatin may not be of a magnitude that was clinically significant in the group as a whole, but the number of individuals who experienced decreases of a degree that was likely to constitute a clinically significant difference was greater for those receiving simvastatin than placebo. The overall effect of simvastatin on negative affect appears to involve a time-limited increase in the probability that negative events will lead to significant negative affect, especially for the moderate and high thresholds. Although the statistical models suggest that the negative effect of simvastatin on these parameters is no longer significant after long-term administration of the drug, further research on the effect of chronic treatment will be needed to probe for longer-term effects.

The findings reported here warrant discussion from a number of perspectives. First, there are questions about the relationship between these observations and long-standing questions about depression as an adverse effect of statins and other cholesterol-lowering treatments. It is possible that the affective toxicity observed with diary data reflects mechanisms that lead to the onset of clinical depression in the vulnerable individuals who may be most likely to experience statin-related depression.[42] From this perspective, it is possible that the suggestions in the literature about the associations between cholesterol-lowering treatments and clinical depression may represent the elusive "tip of an iceberg," reflecting other less-pervasive effects on affective processes that are operative far more frequently. Second, there may be questions about the interpretation of the relationships between affects and events. Although it may be intuitively reasonable to interpret these associations as a reflection of the effect of events on affects, this interpretation could be challenged. An alternative explanation is that the recollection and report of events and affects could be sensitive to subjects' affect at the time that entries were recorded. Third, the fact that significant findings emerged from this study in spite of ongoing controversy about the affective toxicity of statins suggests the power of the methods, including the use of daily diaries and mixed-effects models for statistical analysis.

There must also be questions about the mechanisms that underlie the findings reported here. It is not clear whether they reflect effects attributable to simvastatin as a specific medication, to the class of statins, or to all effective cholesterol-lowering interventions. Moreover, the literature suggests that statins may have effects related to the inhibition of cholesterol synthesis in the brain as well as the periphery[43,44,45] and that they may have direct physiological effects on blood vessels and other tissues independent of those effects that are mediated by lowering plasma cholesterol.[46,47,48,49] Therefore, it is not clear whether the affective outcomes related to simvastatin follow directly from decreases in plasma cholesterol or whether the affective outcomes and the changes in serum cholesterol reflect separable processes. Finally, there must be questions about generalizability to other statins and other treatments. Of the statins in clinical use, simvastatin (as well as lovastatin) is relatively lipophilic and able to cross the blood-brain barrier, whereas others are more hydrophilic.[50] Hence, depending upon the mechanisms that are operative, simvastatin may be more likely than other agents to cause central nervous system effects. These questions are not just relevant to the basic neurobiology of affect, they also represent problems for clinical management of patients for whom significant affective symptoms arise during treatment with simvastatin or related agents. From a pragmatic perspective, current knowledge is not adequate to recommend any specific intervention for patients who experience decreased positive affect, increased reactivity to negative events, or depression while taking simvastatin. Alternative clinical approaches include changing to a different statin that is less likely to cross the blood-brain barrier, changing to a different class of cholesterol-lowering medication, or addition of an antidepressant or other treatment directed toward the mood-related symptoms.

In summary, the findings reported here support the hypothesis that simvastatin can lead to adverse effects on affect and affective processes. Increasing evidence for the benefits of statins and other cholesterol-lowering treatments suggests the importance of further research targeted toward recognizing these symptoms and developing interventions to ameliorate them as components of strategies to improve acceptance of and adherence to more-widespread use of statins.

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