University of Amsterdam
Statin Associated Psychological and Neurological Adverse Drug Reactions
Are The Increased Number Of Prescriptions Of Statins Harming The Healthy?
Author:
Wiebe N. Kremer (10197605)
Specialisatie: Klinische Neuropsychologie
Supervisor:
Huib Van Dis
Contents
Introduction 1
The Effects of Statins on Cognitive Skills 2
The Effects of Statins on Sleep 3
The Effects of Statins on Erectile Dysfunction 5 The Influence of Statin Therapy on Peripheral Neuropathy 6
Conclusion 7
Discussion 8
Statin Associated Psychological and Neurological Adverse Drug
Reactions: Are The Increased Number Of Prescriptions Of Statins
Harming The Healthy?
Wiebe Kremer
University of Amsterdam
This review examined the association between adverse psychological drug reactions and statins. The prescription of this medication is rapidly increasing and knowledge of these side effects is thus becoming more and more relevant. Most commonly reported psychological side effects were reviewed here, including cognitive impairment, sleeping problems or insomnia, and erectile dysfunction. Furthermore, a possible association between neuropathy and statins was examined. Results suggested that statins are associated with cognitive impairment and neuropathy, are not associated with erectile dysfunc;tion, and heterogenous results for sleeping problems and insomnia. Considering these results it does not seem to be a good idea to broaden the guidelines for prescribing statins since this way we might risk harming healthy people who do not need this medication. People that are at an elevated risk of coronary heart disease naturally need to be prescribed this medication, but doctors and psychologists treating these patients should be vigilant in order to detect these adverse psychological drug reactions to help alleviate them.
Introduction
Inhibitors of HMG-CoA reductase, also known as statins have so far been very successful in lowering cholesterol and reducing risk of cardiovascular disease in several clinical trials using thousands of patients (Wilt et al., 2004). The last major revision of the US guidelines, in 2001, increased the number of Americans for whom statins are recommended from 13 million to 36 million, most of whom do not yet have but are estimated to be at moderately elevated risk of developing coronary heart disease. If these same guidelines would be applied in the Netherlands it would mean that 96% of men aged 55 and above would be prescribed statins (Kavousi et al., 2014). Some doctors have challenged the validity of the U.S. clinical practice guidelines recommending the expanded use of statins in healthy people since this guideline greatly increases the rate of overdiagnosis. A narrow definition of overdiagnosis would be that “people without symptoms are diagnosed with a disease that ultimately will not cause them to experience symptoms or early death” (Moynihan, Doust, & Henry, 2012). However, when one looks at this problem more broadly, it can also refer to related problems such as overmedicalisation and subsequent overtreatment, shifting thresholds, and all processes that contribute to reclassifying healthy people with mild problems or low risk as sick.
One major factor that plays a role in the increasing rate of overdiagnosis is excessively widened definitions of common diseases or conditions such as hypercholesterolemia. Such changes in diagnostic criteria are commonly made by panels of health professionals with financial ties to companies that benefit directly from any broadening of the group of
poten-tial patients (Moynihan et al., 2013). Other ways that the pharmaceutical industry obtains wide-reaching influence is through funding of direct-to-consumer advertising, research foundations, disease awareness campaigns, and medical edu-cation. Therefore some research conducted in this area must be interpreted carefully. Even though the current approach has reduced suffering and has prolonged life for some, it has also turned life into a complicated web of chronic conditions for others prescribed this medication, while not even needing it.
The prescription of this medication causes no controversy for adults aged between 30 and 80 years old who already have occlusive vascular disease, since statins confer a total and cardiovascular mortality benefit (Wilt et al., 2004). However, there is little evidence that much benefit is to be gained by prescribing this medication to healthy people who have mod-erately elevated risk of developing coronary heart disease. Yet there are some serious psychological adverse effect associated with the use of statins (Tuccori et al., 2008).
Generally, the use of this medication seems to be well tolerated by patients, but some serious adverse drug reactions (ADRs) do occur. These side effects mostly affect muscles, liver and kidney. However, since lipids account for about half of the dry matter of the CNS and are integral components of myelin sheaths and synapses, recent interest has been focused on potential risk of psychological adverse reactions to statins (Tuccori et al., 2008). Some of the most reported adverse effects are cognitive impairment, decrease in sleep quality or insomnia, and erectile dysfunction (Lareb, 2014). As the use of statins increases, such individual problems may arise more
frequently, and early recognition may lead to their alleviation. Even though these side effects seem to be rare, the highly increased number of prescriptions for this medication make it very relevant to be aware of which psychological domains might be affected by the administration of this drug. Therefore the aim of this review will be to investigate the hypothesis that statins might be associated with psychological ADRs, and to examine which of the possible side effects are most common.
Since statins might influence the central nervous system this might also be the case for the peripheral nervous system. It has also been suggested that long-term statin therapy will increase the risk of developing peripheral neuropathy (Lareb, 2014). This might provide evidence for the idea that statins might influence the peripheral nervous system. Given the in-creasing number of patients prescribed statins, doctors should be aware of this possible adverse drug reaction. Since patients with this condition often experience unpleasant sensations with no apparent long-term physical effect, they are occasion-ally treated by psychologists, and they should therefore also be aware of this possible association.
The recognition of all these adverse effects is important to clinical neuropsychologists, since they could change a pa-tient’s diagnosis and possible treatment. We will start with one of the most important of these, cognitive impairment possibly being caused by the use of statins. We will then go on to examine the possibility of sleeping problems being associated with statin therapy. Moving our investigation over to the co-occurrence of erectile dysfunction and the prescription of statins and finishing with examining the association between neuropathy and statin therapy.
The Effects of Statins on Cognitive Skills
Current literature has been in conflict with regards to the effect of statins on cognitive skills. Case reports raise the possibility that statins, in rare cases, may be associated with cognitive impairment, though causality is not certain. How-ever, even the FDA has now made changes in the safety label for statins in order to provide the public with more informa-tion for the safe and effective use of statins. These changes are based on FDA’s comprehensive review of the statin class of drugs and suggest that the side effects might not be rare but simply underreported. The main cognitive impairments they report are memory loss and confusion (FDA, 2012). Fur-thermore, some experimental research has also shown that statins might have some negative effects resulting in cognitive impairments. This information can be very useful to psychol-ogists who frequently assess cognitive skills in a population that is prescribed statins. Especially, since the number of people using this drug is rapidly increasing. Thus, if a patient is prescribed statins and shows cognitive impairments that are characteristic of statin use, the prescription could be switched or discontinued to solve this problem.
To examine the possible ADRs, Wagstaff, Mitton, Arvik,
and Doraiswamy (2003) conducted an analysis of 60 case reports of cognitive impairments associated with the use of statins. They searched the MedWatch drug surveillance sys-tem of the Food and Drug Administration (FDA) for report of memory loss associated to statins. Using the preferred terms memory, confusion, Alzheimer, think, cognition, at-tention, and mental , they identified 60 patients who had statin-associated memory loss. For these patients the mean age was 62 years and ranged from 30 to 84 years, and 32 were women, 25 men, and 3 reports did not document sex. The nature of memory loss varied, but most common were short-term memory loss and amnesia. The former was defined as having lost recent memories from daily life and not as a problem with working memory. About 50% of these patients experienced these memory problems within 2 months of the onset of use of statins. No specific memory test results were reported for any of these cases. The types of statin prescribed for these patients were simvastatin (36 patients), atorvastatin (23 patients) and pravastatin (1 patient). The most notable result of this analysis was the fact that of the 33 patients that discontinued the statin therapy, 14 patients showed resolved or improved memory loss problems. Furthermore, of the four reports that described the effects of rechallenge, all reported a reappearance of the memory loss of symptoms. This seems to suggest that statin therapy may in some cases cause cognitive impairment, although causality is not certain. However, since this research is purely descriptive, more experimental research must be explored in order to answer the question of whether statins cause cognitive impairment.
Muldoon et al. (2000) conducted a double-blind investiga-tion of the effects of lovastatin on cognitive functioning and psychological well-being. Participants were recruited from Al-legheny county in south-western Pennsylvania through news-paper advertisements and distribution of posters and study brochures. 209 healthy adults were selected if their serum low-density-lipoprotein cholesterol was higher than 160mg/dL. The participants were assigned randomly to either a 6-month lovastatin therapy condition or the placebo condition. Neu-ropsychological performance was assessed across five cog-nitive performance domains, these include general mental efficiency (Stroop Interference, Trail Making, Digit Vigilance, Letter Rotation), attention (Digit Vigilance, Letter Rotation, Digit Span, Recurring Words), psycho-motor skills (Grooved Pegboard, Elithorn Maze, Digit Symbol), learning (Asso-ciative Learning, Digit Span) and memory (Controlled Oral Word Association, Verbal Recall, Complex Figure). These neuropsychological tests were selected because they are all es-sential for routine daily activities. Assessment was done both at baseline and at the end of the treatment period. Participants in the placebo condition improved on all five performance domains when compared to baseline. This is in line with the expectation that practice has a positive effect on performance. On the other hand, patients treated with lovastatin improved
STATIN ASSOCIATED PSYCHOLOGICAL AND NEUROLOGICAL ADVERSE DRUG REACTIONS 3
only on tests of memory recall. However, when the lovastatin condition was compared with the placebo condition small but significant differences were revealed for tests of attention and psycho-motor speed. Be that as it may, standard neuropsy-chological tests attempt to separate cognitive skills but never fully succeed in doing so, such that individual tests tend to measure more than one particular skill. Therefore the effects of lovastatin that were found here for attentional and psycho-motor skills may not be selective for these distinct cognitive components. Accordingly, more research has to be conducted with a wider range of neuropsychological tests to get a higher degree of certainty as to which cognitive components might be affected by statin use.
Muldoon, Ryan, Sereika, Flory, and Manuck (2004) at-tempted to confirm and extend their previous results by using a wider array of neuropsychological tests and a different type of statin at two different doses. The study included 308 par-ticipants between 35 and 70 years of age, with an average of 54 years, who had mild-to-moderate-hypercholesterolemia, defined as a low-density lipoprotein cholesterol level be-tween 160 and 220 mg/dL. Participants were recruited from Allegheny county in south-western Pennsylvania through media advertisements and distribution of posters and study brochures. Using a double-blind design, participants were as-signed randomly to daily treatment with 10 mg of simvastatin, 40 mg of simvastatin or placebo. A neuropsychological test battery similar to the one used in the study described above was used to assess cognitive functioning both at baseline and at end of the treatment period. However, some small changes were made, most notably new tests were added that have high sensitivity to small differences in cognitive perfor-mance among high-functioning persons (Mirror Tracing and 4-Word Short-Term Memory). The tests used in the previous study were simply categorized as sensitive and statin-insensitive tests based on whether significant differences were found between the placebo and treatment condition. This way the earlier findings could be confirmed and extended. When the treatment group was compared with placebo, small but significant effects of simvastatin were found both on the tests that were previously discovered to be sensitive to statins and on the new tests that were added for this experiment. No significant difference was found on tests that were previously established to be insensitive to statins. It must be noted that the significant effects that were found for simvastatin on cog-nitive performance were very small and only shown by lack of improvement through practice, as was the case in the placebo condition. Furthermore the results revealed that a 40-mg dose of simvastatin did not have greater effect on cognitive performance than the 10-mg dose. To sum it up, statins seem to have a small but negative effect on cognitive performance on neuropsychological tests that are sensitive to statins.
The evidence so far seems to agree that statins have a negative effect on cognitive functioning and may result in
serious cognitive impairment (as described in some case re-ports). However, even though effects of statins on cognitive functioning seem to be negative, the effects found in experi-mental studies are small and the clinical significance of them is thus still unsure. Some case reports seem to suggest that some people found themselves impaired to a level where they couldn’t successfully complete their daily activities. On the other hand, the effects found in experimental studies have often divided cognitive functioning into several domains, for example memory and attention. However, the neuropsycho-logical tests that are used in these studies tap into a variety of skills and therefore can’t offer evidence that the cognitive effects of statins are specific to one or two cognitive domains. Therefore future research might do well to focus more on the degree to which use of statins might affect performance in a daily setting that requires cognitive skills. Additionally, other research has also shown that statin therapy seems to decrease the risk of developing Alzheimer’s disease (Haag, Hofman, Koudstaal, Stricker, & Breteler, 2009) and also slows down the process of cognitive deterioration that generally accom-panies this disease (Sparks et al., 2006). These finding are naturally very contradicting and thus more research is needed to reveal the mechanism by which statins might affect cogni-tive ability to help explain these contradicting results. One of the suggestions of how this mechanism might work is that statins might alter neuronal function through effects on brain cholesterol metabolism (Koudinov & Koudinova, 2001). If this is indeed how statins affects cognitive skill, many other domains of the psychological function could also be affected. Therefore next section will look at the seemingly common side effect of sleep impairment that can have a very negative impact on life.
The Effects of Statins on Sleep
Recently a number of patients have reported mild to moder-ate cases of insomnia that were associmoder-ated with a recent start of statin therapy. Also in some clinical cases long-term ad-ministration of statins has been reported to be associated with moderate to low incidence of insomnia. However, this was only the case for patients taking lovastatin, whereas patients taking pravastatin did not report any decrease in sleep dura-tion. A possible reason for this difference in ADRs could be that these medications have different degrees of lipophilicity. However, for case reports these side effects have also been reported in combination with other types of statins (Boriani, Biffi, Strocchi, & Branzi, 2001). Therefore, we will examine what role statin therapy can possibly play in the development of sleeping problems and what mechanism might be at the root of this problem.
Vgontzas, Kales, Bixler, Manfredi, and Tyson (1991) used a double blind placebo-controlled design to evaluate 12 nor-mal subjects (6 men and 7 women) in a sleep laboratory study. The participants were randomly assigned to either a
lovastatin condition (lovastatin) or a pravastatin condition (40 mg pravastatin). The protocol for both groups consisted of 22 consecutive nights of which 4 nights were used as a placebo-baseline night, 2 weeks consisted of drug treatment, and 4 placebo-withdrawal nights. Participants slept in the labora-tory from nights 1 to 7, at home from nights 8 to 14, and in the lab again for nights 15 to 22. During each night in the laboratory participants were monitored for 8 hours using an electroencephalogram, electromyogram, electro-oculogram, according to a standard protocol. Sleep efficiency was mea-sured using sleep latency (defined here as the time awake from the beginning of the recording period to sleep onset), wake time after sleep onset, total wake time and number of awak-enings. Furthermore subjective sleep assessment was taken using a sleep questionnaire. Results showed that lovastatin initially didn’t disturb sleep (nights 5 through 7), however with continued administering of the drug (nights 16 through 18) the assessment of wake time after sleep onset increased significantly. On the other hand, the use of pravastatin was not associated with sleep disturbance initially or with contin-ued administration. During the placebo withdrawal no sleep disturbance was found in both of the conditions. However, subjective measures resulted in no significant differences in sleep quality between the two different drugs. In conclusion, these results seem to support the idea that at least some types of statins can cause sleeping problems. A possible reason for the difference in ADRs for this medication is the degree of lipophilicity. Research has revealed that the degree of lipophilicity is a determinant of the rate of absorption and dis-tribution to the central nervous system which then in turn can influence the intensity and duration of the effect of the drug on the central nervous system (Vgontzas et al., 1991). This could possibly account for the difference between lovastatin and pravastatin, since the former of these is highly lipophilic while the latter is hydrophilic. By this logic simvastatin, an-other highly lipophilic medication should also have a negative effect on the sleep efficiency. Therefore the next study that will be discussed will examine the effects of simvastatin on sleep and compare it with pravastatin as was done in this study by Vgontzas et al. (1991).
Eckernäs et al. (1993) set out to examine whether these structurally different statins had an effect on sleep quality and whether this difference in effect could be attributed to the differences in lipophilicity of these medication. To do this, they used a double blind placebo controlled design in which 24 male patients with moderate hypercholesterolaemia received 4 weeks of treatment with equal doses of either sim-vastatin or prasim-vastatin (40 mg a day for both). During this time their sleep quality was measured using a polysomnography and subjective sleep assessments. The results indicated no significant differences between simvastatin, pravastatin, and placebo looking at EEG measures that are considered relevant to insomnia. Subjective rating of sleep quality also showed no
significant differences between the various conditions. Based on these results one would both conclude that statins have no negative effect on sleep quality and that lipophilicity of statins does not translate into an increased number of sleep disturbances, measured either objectively or subjectively. An-other way that the difference found in the study by Vgontzas et al. (1991) can be explained is that not everyone is sensitive enough to the higher degree of lipophilicity of certain statins. Therefore another study should examine whether there is a difference in effect of highly lipophilic and hydrophilic statins within one individual. The next study’s design allows us to examine precisely that.
In order to test the hypothesis that statins with a high de-gree of lipophilicity have a negative effect on sleep quality Ehrenberg et al. (1999) conducted a randomized double blind three-way crossover treatment study with lovastatin, pravas-tatin and placebo. Sixteen participants (11 men and 5 women) were selected from a population of patients attending a Lipid Clinic where the authors of this article were employed. This study consisted of 6 phases, each lasting 4 weeks, coming to a total duration of 24 months. Firstly, participants were given placebo tablets matching tablets of lovastatin and pravastatin for 4 weeks as a way to establish their compliance to the regimen. After this the participants were subjected to the three-way crossover treatment with lovastatin, pravastatin and placebo for 4 weeks each, followed by a 4 week placebo washout period. Sleep quality was measured in the labo-ratory for 2 consecutive nights using a polysomnography. Results showed no significant difference in sleep parameters when lovastatin and pravastatin treatment were compared with placebo. Furthermore no significant differences were found between treatments, although this could also be a result of the small sample size. Nevertheless, 14 out of 16 participants showed abnormal sleeping patterns that could account for insomnia but most likely predate the use of statins. The fact re-mains that some patients report being unable to perform their work or daily activities right after the onset of statin therapy. To their knowledge this decrease in their ability to perform these activities is attributable to a lack of sleep. However, it might also be possible that statins directly affect daytime performance which could explain the symptoms described in these case reports. We will now examine this possible explanation for this ADR associated with statin therapy.
Richardson et al. (1992) researched the influence of lo-vastatin and pralo-vastatin on sleep quality and daytime perfor-mance. Lipophilicity has previously been suggested to be a determining factor for whether a HMG CoA Reductase inhibitor will have a negative effect on sleep. Just as the previ-ous studies, this study also examined this possible difference in ADRs for statins. Furthermore, daytime performance is known to be determined partially by sleep quantity and quality (Johnson et al., 1982). Therefore performance on cognitive tasks during the daytime will also be assessed in order to
STATIN ASSOCIATED PSYCHOLOGICAL AND NEUROLOGICAL ADVERSE DRUG REACTIONS 5
examine whether statins affect this performance in any way. 59 male patients were assigned randomly to either a lovastatin, pravastatin (both 40 mg) or placebo condition. Sleep quality was measured both subjectively using sleep questionnaires administered daily and objectively using a polysomnogra-phy for two consecutive nights. Daytime performance was measured using 4 neuropsychological tests: divided attention, vigilance, simple reaction time, and choice reaction time. Results showed no significant differences in sleep quality for lovastatin or pravastatin when measured objectively. On the other hand, subjective measurements showed a significant increase in number of awakenings and a significant decrease in sleep quality. None of these differences were reported by the participants in the pravastatin condition, but the placebo condition also reported a decrease in sleep quality. This could be an indicator that the decrease in sleep quality is more of a placebo effect than a real side effect of the prescription of statins. Additionally, lovastatin did significantly affect daytime performance. Specifically divided attention and vigi-lance were affected as was the global performance on these 4 tests. These differences were not found for participants in the provastatin and placebo condition. These results converge with the evidence provided earlier of the effects of statins on cognitive performance.
To conclude, even though case reports describe negative effects of statins on sleep quality experimental evidence seems in conflict on whether this possible adverse drug reaction is associated with statins or not. This conflict might be explained by the fact that some of these studies are biased because they were funded by a pharmaceutical company. These studies might have been set up in such a way that there was a smaller chance of finding negative side effects.
Notwithstanding, sleep was affected in one of the studies described here, which might support the claim that statin use might in rare cases result in a decrease in sleep quality. The possibility that this might only occur in rare cases would help explain why not all of these studies found this effect, since some of these studies had small sample sizes. However, it could also be the case that this side effect is simply under-reported. Therefore doctors and psychologists prescribing or treating patients with this medication should be aware of this possible side effect and ask for it in order to help alleviate it. Another type of adverse drug reaction that has been frequently reported is Erectile Dysfunction (ED) and will therefore be discussed in the next section.
The Effects of Statins on Erectile Dysfunction Considering the widespread use of statins and the case reports indicating this medication might cause erectile dys-function (ED) suggests a large number of people might be affected by this side effect. Since this problem is often under-reported, doctors and psychologists should be aware of this possible side effect when treating their patients and ask them
about it, especially since this particular ADR could be very damaging to someones sex life. The sooner these problems are recognized, the sooner this problem can be alleviated. Fur-thermore, since there are alternative agents that could be used to lower lipid concentrations that can avoid the development of impotence these alternatives can be prescribed instead. However, since there is still plenty of conflicting research circulating it is important to firstly examine the claim that these two factors are associated with each other. We will start by looking at some data on the quantity and characteristics of these case reports and later on move on to more experimental research.
Carvajal et al. (2006) carried out a study with the goal to explore the basis of the claim that impotence and statin use are associated. To do this, they used data from spontaneous re-ports. They analyzed cases of impotence using data collected by the French and Spanish pharmacovigilance systems. The number of cases as well as the consumption data were used to estimate the cumulative reported incidence of impotence. In the database of the Spanish pharmacovigilance system 38 cases of impotence were associated with statins. In 93% of cases symptoms completely disappeared after the drug was withdrawn. With regard to the consumption data, the median induction period was 16.5 days, which suggests that there was a temporal sequence of events in all of these cases. In the French database 37 more cases of impotence as a result of statin therapy were found. Here again symptoms completely disappeared in 85% of these cases. Furthermore, 5 of these patients were re-challenged with statins and the symptoms re-occurred, possibly indicating that statins were the cause of the symptoms of ED. No significant differences were found between types of statins. Even though this data seems to suggest a link between statin use and ED more experimental research is needed to confirm these suspicions.
One of the largest survival studies with simvastatin was conducted by a research group in Scandinavia (Group, 1994) to examine if simvastatin is safe and if it improves survival in patients with coronary heart disease. 4444 patients with angina pectoris or previous myocardial infarction and serum cholesterol of 5.5-8.0 mmol/L on a lipid lowering diet were selected and randomly divided over a simvastatin and placebo condition. Erectile dysfunction was assessed using a number of spontaneous reports of ED. Results showed that simvas-tatin was successful in improving survival in coronary heart disease patients. Besides this, they also found that more cases of ED were reported in the simvastatin condition (37 vs. 28). However, the results did not reveal any significant difference between the simvastatin and placebo condition. This suggests that the increase in ED might simply be a placebo effect. The fact that there are still a good amount of cases of ED in this sample suggests that perhaps other factors could explain the reports of ED in the case reports discussed before. One of the possibilities is simply the fact that impotence is not
uncommon in middle aged and elderly men. In other words, the groups most frequently prescribed statins. We continue to more research that could possibly resolve this issue.
The goal of the prospective observational study performed by Solomon et al. (2006) was to examine the possible rela-tionship between erectile dysfunction to cardiovascular risk factors and specific drug therapies before and after 6 months of statin therapy. Participants were 93 men attending car-diovascular risk clinics. Erectile function of these men was measured using the International Index of Erectile Function (IIEF) before treatment with statin and after 6 months of statin therapy. Prior to treatments and after 6 months of statin therapy cardiovascular risk factors and drug therapies were assessed. IIEF scores after statin therapy significantly reduced when compared to scores at baseline. This shows that ED problems increased during statin therapy since a low score on this questionnaire is indicatory of more severe ED. In order to examine whether some other factors might explain the increase in cardiovascular risk factors such as age, smoking and diabetes were also assessed before and after statin therapy. Multiple regression showed that ED is more likely in patients with these risk factors. This suggests that the previous results that suggest statins cause ED might not be representative of the whole picture, but that other factors play a role in the higher number of ED in patients prescribed statins. Most likely endothelial dysfunction was caused by these risk factors ultimately resulting in ED. If this is indeed the case one might think that if statins effectively lower patients their cholesterol, ED might also improve. We now examine a study that tries to answer this question.
Saltzman, Guay, and Jacobson (2004) designed a study with the aim of determining whether the use of statins im-proves erectile function in men with hypercholesterolemia as the only risk factor for erectile function, by lowering choles-terol. 9 men with organic ED and hypercholesterolemia as only risk factor for ED by history were selected to participate in this study. Organic ED was assessed objectively using a RigiScan in order to measure nocturnal penile tumescence and rigidity. Furthermore, as an objective measure the participants had to fill in the Sexual Health Inventory in Men question-naire. Atorvastatin was given to the participants in order to decrease total cholesterol to less than 200 mg/dl and low-density lipoprotein cholesterol to less than 120 mg/dl. Results showed a significant decrease in both total and lipoprotein cholesterol. Furthermore, they also revealed a significant im-provement on the Sexual Health questionnaire. Clinically 8 of 9 men had improved erectile function during intercourse that was adequate enough for penetration. Objectively, results of the RigiScan also showed significant improvement in average penile rigidity at the base and tip after the treatment with atorvastatin. To conclude, these results seem to indicate that treating hypercholesterolemia with statin may improve ED while also reducing cardiovascular risks.
On the whole, it seems that symptoms of ED in patients being prescribed statins seems more of a characteristic of the population prescribed this medication then an adverse reaction to the medication. Even though we have seen here that there are some case reports that have associated the use of statins with ED, experimental research seems to suggest that the cardiovascular risk factors are more likely to be explanatory of the symptoms of ED. The last article discussed here even seems to suggest that if statins are able to lower the cholesterol to a certain level, the erectile function might improve.
The Influence of Statin Therapy on Peripheral Neuropathy
Peripheral neuropathy is a general term which includes a variety of conditions characterized by paraesthesias (a sen-sation of tingling, tickling, prickling, pricking, or burning of a person’s skin with no apparent long-term physical ef-fect), sensory loss, muscle weakness, and hyperaesthesias (a condition that involves an abnormal increase in sensitivity to stimuli of the sense) of the extremities. Peripheral neuropathy is mentioned in the summary of product characteristics (SPC) of atorvastatin as an uncommonly occurring adverse reaction. The SPC of simvastatin mentions peripheral neuropathy as an adverse reaction, which occurred in non-controlled trials and post-marketing surveillance. SPCs of the other HMG-CoA-reductase inhibitors don’t report peripheral neuropathy as a possible side effect. If experimental research finds a link between peripheral neuropathy and statin therapy this might be interpreted as proof for the idea that statins might influence the peripheral nervous system.
Since these symptoms are very hard to treat physically, patients with these symptoms sometimes end up with a psy-chologist to help them deal with their pain more effectively. However, psychologists should be aware that if their patient is also prescribed statins, their condition might be caused by this medication. Discontinuation of this drug could be more effective than psychological treatment. Therefore, psychol-ogists should be aware of this possible side effect. We will now examine whether peripheral neuropathy and statins are really associated and if they are, when the effects of statins are commonly observed.
De Langen and Van Puijenbroek (2006) examined the database of reported ADRs of the Netherlands Pharmacovigi-lance Centre Lareb for reports of neuropathy associated with the use of statins. This possible relationship was assessed mathematically by computing the reported odds ratios (ROR). This odds ratio is used to compare the frequency of an ADR for a particular drug with the frequency of reports of that ADR for all other drugs in the database. If the ROR is sta-tistically significant this might indicate that use of a specific medication may have a higher risk for that particular adverse drug reaction. However, it does not necessarily indicate a causal relationship. The database, which ranged from 1984
STATIN ASSOCIATED PSYCHOLOGICAL AND NEUROLOGICAL ADVERSE DRUG REACTIONS 7
to 2005, received 17 reports of neuropathy and 2 reports of aggravation of polyneuropathy associated with the use of statins. 9 of these reports concerned simvastatin, 6 ator-vastatin, 3 pravastatin and 1 rosuvastatin. After adjustment for the influence of age, gender, and the use of antidiabetic medication, the ROR for neuropathy was 3.7. This shows that neuropathy is significantly more reported during treatment with statins when compared with any other drug class in the Lareb database. Other characteristic of these reports also support an association between the symptoms and the use of statins. For example, symptoms improved or disappeared in seven cases that stopped taking this medication. This study gives some preliminary proof for an association between statin use and polyneuropathy. However, since the authors used the Lareb database, cases were only compared to people who were also taking other medications. Therefore, the odds ratio reported in this study might be higher than they truly are in the whole population. It might then be a good idea for another study to also include a sample of the general population in order to come to a more reliable conclusion.
Gaist, Rodríguez, Huerta, Hallas, and Sindrup (2001) ex-ecuted a population-based dynamic cohort study based on data from general practices in the United Kingdom from 1991 to 1997. With this design they aimed to estimate the risk of peripheral neuropathy associated with lipid-lowering drugs (including statins). Three cohorts of individuals were identified: people who received at least one prescription for lipid-lowering drugs, people who had a diagnosis of hyper-lipidaemia but who had not been prescribed lipid-lowering medication, and lastly a group of individuals from the general population. Results showed that the incidence rate of periph-eral neuropathy in users of lipid-lowering drugs was higher than in the non-treated cohort and the general population cohort. This raised risk was confined to users of statins and not to users of other lipid-lowering medications (odds ratio: 2.5, CI 0.3-14.2). Unfortunately, because of the very wide confidence interval no solid conclusion can be made based on these results. We will therefore look at another study that might improve on these results in an attempt to make the association between statin use and peripheral neuropathy more certain.
Gaist et al. (2002) performed a case control study in the county of Funen, Denmark to estimate the relative risk of neuropathy in users of statins. They used a population-based registry to identify first-time-ever cases of idopathic polyneu-ropathy registered from 1994 to 1998. Each case was then validated according to predefined criteria and 25 control sub-jects were randomly selected from the background population and were matched for age, sex, and calendar time. Cases were further classified as definite, probable, and possible. A prescription registry was then used to estimate the odds ratio of use of statins in cases of idiopathic neuropathy compared with the control subjects. Results showed that the odds ratio
linking statin use to idiopathic neuropathy was 3.7 for all cases which incidentally is the same odds ratio found by De Langen and Van Puijenbroek (2006). The odds ratio for definite cases was 14.2. For patients who had been treated with statins for a period longer than 2 years, the odds ratio of definite idiopathic neuropathy was 26.4. Not only do these results show that statin therapy and neuropathy seem to be linked, it also indicates that long-term exposure to statins may substantially increase the risk of developing neuropathy.
All evidence so far seems to suggest statin use is associated with peripheral neuropathy in rare cases. Furthermore, the re-search discussed indicates that this risk increases when statins are used for a longer period of time. This could be interpreted as further proof for the idea that statins affect the peripheral nervous system. Even though the adverse drug reaction is rare, because of the increasing number of patients using statins and the irreversibility of neuropathy, doctors and psychologists alike should be aware of the possible role statins can play in the development of neuropathy. However, since evidence of this possible link has only been found recently, it might also be the case that these symptoms are simply under-reported.
Conclusion
To sum it all up, this review has revealed that statins cer-tainly have some negative psychological side effects. How-ever, not all of the side effects that were most commonly described in case reports were backed up by experimental evidence. One of the ADRs to statins that was supported by clinical trials was cognitive impairment. Even though the effects found in these studies were small, they were nonethe-less significant. The findings were not able to point to one particular cognitive domain that was affected, since the tests that were used can’t measure one cognitive skill exclusively. The evidence regarding the association between statins and sleep seems mixed. Some experimental evidence seems to back up this association, like Vgontzas et al. (1991), while others debunk this claim. A possible explanation for this discrepancy is that there might be an association, but only in rare cases. Since most of these studies used small samples, not every one of them would have detected this association. Additionally, the last experiment discussed in this section in-dicated that the use of statins resulted in a decrease in daytime performance which is further proof for the idea that statins may cause cognitive impairment.
We also examined the possibility that statins caused ED in male patients. Results from this research seem to suggest that the higher number of reports of ED in this population can simply be explained by the fact that there is a naturally higher rate of ED in this population. Characteristics of this population that seemed to be associated with the development of ED are cardiovascular risk factors such as age, smoking and diabetes. Finally, we revealed that statin therapy is associated with peripheral neuropathy. This heightened risk increased
even more when patients were exposed to this medication for a longer period of time (longer than 2 years).
Evidence for cognitive impairment as a result of statin ther-apy suggests that statins might really have an influence on the central nervous system, whereas the link between statins and peripheral neuropathy supports the idea that statins influences the peripheral nervous system aswell.
The proof that there are some adverse psychological effects (mainly cognitive) makes the broadening of guidelines that result in a higher number of prescriptions for statins doubtful as the right thing to do. The risks that accompany may not out-weigh the benefits that they provide, especially for people that are only prescribed this medication as a primary prevention for developing cardiovascular disease and are thus not really at any reasonable risk yet. Therefore we should be careful with the broadening of these guidelines to avoid harming the healthy. Furthermore, doctors and psychologists, who both frequently treat patients from the population generally prescribed statins (mainly men above the age of 55), should be aware of these possible psychological side effects and ask their patients about them to alleviate possible negative side effects as quickly as possible.
Discussion
Not all research is perfect, and this is also the case with the studies that are discussed in this review. We will therefore examine some of the shortcomings of these experiments and suggest how future research could improve on them.
Firstly, many of the articles used a very small sample size, for example between 10 and 15 people. One of the disad-vantages of this approach is that if sample sizes are small, it will always be difficult to find significant results from the data. The reason for this is that most statistical tests normally require a large sample size in order to ensure a representative distribution of the population. Furthermore, to be able to generalize to the population, the sample of participants that was tested must be representative of the population. Generally, the smaller the sample size, the smaller the chance that your sample will be representative of the population. This would also mean that if side effects are rare in the population, they would also be rare in the sample. Therefore, the smaller the sample, the smaller the chance that you will be able to detect these rare side effects. Future research should therefore at-tempt to recreate some of these studies but with larger sample sizes to obtain a higher amount of certainty of conclusions previously drawn.
Another factor that might limit the certainty of the results that are discussed here is the difference in degree of lipophilic-ity of statins. About half of the dry matter that makes up our CNS is accounted for by lipids. They are integral components of myelin sheaths and synapses and could therefore possibly cause change in the brain, resulting in psychological side effects. However, not all statins have the same degree of
lipophilicity and thus might affect the CNS in different ways (Tuccori et al., 2008). It therefore might be an oversimpli-fication to conduct and experiment with one type of statin for adverse drug reactions and then go on to generalize these results to all statins. Therefore it might be a good idea to always include statins with different degrees of lipophilicity. The same is true for the peripheral nervous system, when research is conducted to examine symptoms like peripheral neuropathy.
Furthermore, a lot of the research in this area is funded by the pharmaceutical companies that sell the medication. This means that positive results would be best for them and this might indirectly affect the way the results of these studies are represented. More independent research is thus the most desirable way to prevent any possible bias by pharmeutical companies.
One of the strengths of some of the case reports was the fact that some of the patients that experienced adverse effects were rechallenged with the drug. This was to verify if it was indeed the medication that was causing the side effect. None of the experimental studies discussed in this review used this ABAB design. In order to be sure that possible side effects are indeed caused by statins, it might be a good idea to also employ this design in future research when it is possible.
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The E
ffects of Lovastatin and Pravastatin on Cognitive Functioning and
Sleep Quality
Wiebe N. Kremer
University of Amsterdam
Supervised by Huib van Dis
Introduction
The presciption of HMG-CoA reducatase inhibitors (also more commonly know as statins) has been rapidly increas-ing the last couple years. The main reason for this is the broadening of guidelines for prescribing this medication. For example, in 2001 a revision of the US guidelines increased the number of Americans for whom statins are recommended from 13 to 36 million, most of whom do not yet have but are estimated to be at moderately elevated risk of developing coronary heart disease (Kavousi et al., 2014). Some doctors have questioned the validity of the changes in these guide-lines. Even though statins have so far been very successful in lowering cholesterol and reducing risk of cardiovascular disease in clinical trials using thousands of patients (Wilt et al., 2004), there is little evidence that there is that much benefit to be gained by prescribing this medication to healthy people who have moderately elevated risk of developing coronary heart disease (primary prevention). Yet there are some serious psychological adverse effects associated with the use of statins (Tuccori et al., 2008).
Case reports reveal that some of the most common psy-chological adverse effects are cognitive impairment, sleeping problems or insomnia, and erectile dysfunction (Lareb, 2014). Results from experimental studies suggested that statin ther-apy was indeed associated with cognitive impairment, but it was not yet entirely clear what cognitive domains were most affected and what the clinical relevance was of this decrease in performance. Evidence for sleeping problems as a result of statins is still heterogeneous, some studies reporting decrease in sleep quality while others report no change in sleep quality. Furthermore, one study performed by Richardson et al. (1992) suggested no effect association of statins with sleep but it did show a decrease in daytime performance, which is convergent with evidence on cognitive impairment. Therefore we will include both these factors (cognitive functioning and sleep quality) in this new study in order to verify and extend results from previous studies. The reason for studying these two side effects together is because sleep quality can direct negative influence on daytime cognitive performance (Johnson et al., 1982). This way we can see that if statins are associated with cognitive impairment if this directly attributable to statins or also partially through a decrease in sleep quality.
Another factor that has been proposed to play a role in statins and adverse drug reactions, is the degree of lipophilic-ity. It has been suggested that statins with a higher degree of lipophilicity are more likely to provoke adverse effects because they might be more likely to affect the CNS (Carvajal et al., 2006). This effect has indeed been observed by some but not by others. It might be possible that statins with a high degree of lipophilicity cause side effects in some but not in others. We will therefore select statins with both a high and low degree of lipophilicity.
One of the strong arguments made in some of the case reports concerning the association between adverse drug re-actions is the fact that patients that are rechallenged with the medication experience the adverse drug reactions again. This seems to be further proof for the idea that it is indeed statin therapy causing these symptoms. We will therefore expose each participant to each medication twice in order to see if this medication is indeed the cause of possible side effects. However, in this case instead of no medication before the rechallenge, patients will be prescribed a placebo. This way we will be more certain that is indeed the medication caus-ing the side effects and we can control for any confounding variables.
Methods
Subjects will be generally healthy men and women with mild-to-moderate hypercholesterolemia, defined as a low-density lipoprotein (LDL) cholesterol level between 160 and 220 mg/dL. Participants will be recruited from all over the Netherlands by mass mailings of the study brochure and place-ment of media advertiseplace-ments.
100 male and 100 female patients will be selected and will be assigned randomly to either a lovastatin, pravastatin (both 40 mg) condition. A measurement of their sleep quality and cognitive functioning will be taken at baseline. They will then be pescribed one of the two statins for 6 months and measured again at the end of this period. In the next phase they will be prescribed a placebo for the same amount of time and measured again at the end of this period. The process will then be repeated and measurements will be taken after each phase (see table 1).
2 WIEBE N. KREMER
sleep questionnaires administered daily and objectively using a polysomnography for five nights (one night for each phase). Daytime performance will be measured using four neuropsy-chological tests: 15-Words Test (Memory), Wisconsin Card Sorting Test (Executive Functioning), Stroop Color-Word Test (Attention), and Corsi-Blocks Test (Visual Short-Term Memory and Working Memory).
Data analyses
To analyze the results we will conduct a MANCOVA anal-ysis to detect any significant differences between group for all the measurement discussed earlier. Both age and sex will be used as covariates in order to control for these possibly confounding factors.
Interpretation of Possible Results
We expect statins to have a negative influence on both performance on neuropsychological tests as on sleep qual-ity when compared with the placebo phases of this study. However we also expect differences between the two types of statins. Lovastatin which is a statin with high degree of lipophilicity is expected to have more of a negative effect on our outcome measures then pravastatin, which has a much lower degree of lipophilicity. The reason for this expectation is that because of the high degree of lipophilicty of lovas-tatin it would be likely to affect the central nervous system more strongly than a statin with a low degree of lipophilicity (pravastatin in this case).
If this is indeed the case these results would not only prove that statins can a have negative effect on psychological func-tions, such as cognitive functioning and sleep, but also that this effect is caused by directly influencing the central nervous system.
Table 1 Study design
Group Baseline Period 1 Period 2
Period 3 Period 4 1 Baseline Lovastatin Placebo Lovastatin
Post-treatment 2 Baseline Pravastatin Placebo Pravastatin
Post-treatment
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Biological rhythms, sleep, and performance, 111–141.
Kavousi, M., Leening, M. J., Nanchen, D., Greenland, P., Graham, I. M., Steyerberg, E. W., . . . Franco, O. H. (2014). Comparison of application of the acc/aha guidelines, adult treatment panel iii guidelines, and european society of cardiology guidelines for cardiovascular disease prevention in a european cohort. JAMA, 311(14), 1416–1423.
Lareb. (2014, June). Bijwerkingen van statines.
Richardson, G. R., Sullivan, J. P., Lee, R. M., Roth, T., Merlotti, L., & Roehrs, T. (1992). Comparative effects of pravastatin and lovastatin on nighttime sleep and daytime performance. Clinical cardiology, 15(6), 426–432.
Tuccori, M., Lapi, F., Testi, A., Coli, D., Moretti, U., Vannacci, A., . . . others (2008). Statin-associated psychiatric adverse events. Drug safety, 31(12), 1115–1123.
Wilt, T. J., Bloomfield, H. E., MacDonald, R., Nelson, D., Rutks, I., Ho, M., . . . Sales, A. (2004). Effectiveness of statin therapy in adults with coronary heart disease. Archives of Internal Medicine,
