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LITERATURE ON STATINS: Cognition & Mental Impairment

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LNM Radio Network

Statin-associated adverse cognitive effects: survey results from 171 patients Pharmacotherapy. 2009 Jul ;29(7):800-11. PMID: 19558254 Department of Medicine, University of California-San Diego, La Jolla, California 92093-0995 RESULTS: 128 patients (75%) experienced cognitive ADRs determined to be probably or definitely related to statin therapy. Of 143 patients (84%) who reported stopping statin therapy, 128 (90%) reported improvement in cognitive problems, sometimes within days of statin discontinuation (median time to first-noted recovery 2.5 wks). Of interest, in some patients, a diagnosis of dementia or Alzheimer’s disease reportedly was reversed. Nineteen patients whose symptoms improved or resolved after they discontinued statin therapy and who underwent rechallenge with a statin exhibited cognitive problems again (multiple times in some). Within this vulnerable group, a powerful relationship was observed between potency of the statin and fraction of trials with that agent resulting in cognitive ADRs (p<0.00001). Quality of life was significantly adversely affected for each of the seven assessed domains (all p<0.00000001).CONCLUSION: Findings from the survey suggest that cognitive problems associated with statin therapy have variable onset and recovery courses, a clear relation to statin potency, and significant negative impact on quality-of-life. Administration of a patient-targeted questionnaire is a feasible approach that provides a useful complement to other ADR surveillance approaches. Pharmacotherapy.2009 July
JAMA Intern Med. 2015;175(8):1399-1405.
Importance  Reports on the association between statins and memory impairment are inconsistent.
Objective  To assess whether statin users show acute decline in memory compared with nonusers and with users of nonstatin lipid-lowering drugs (LLDs).
Design, Setting, and Participants  Using The Health Improvement Network database during January 13, 1987, through December 16, 2013, a retrospective cohort study compared 482 543 statin users with 2 control groups: 482 543 matched nonusers of any LLDs and all 26 484 users of nonstatin LLDs. A case-crossover study of 68 028 patients with incident acute memory loss evaluated exposure to statins during the period immediately before the outcome vs 3 earlier periods. Analysis was conducted from July 7, 2013, through January 15, 2015.
Results  When compared with matched nonusers of any LLDs (using odds ratio [95% CI]),

a strong association was present between first exposure to statins and incident acute memory loss diagnosed within 30 days immediately following exposure (fully adjusted, 4.40; 3.01-6.41). i.e. a 4-fold higher risk of acute memory loss

This association was not reproduced in the comparison of statins vs nonstatin LLDs (fully adjusted, 1.03; 0.63-1.66) but was also present when comparing nonstatin LLDs with matched nonuser controls (adjusted, 3.60; 1.34-9.70). The case-crossover analysis showed little association.
Conclusions and Relevance  Both statin and nonstatin LLDs were strongly associated with acute memory loss in the first 30 days following exposure in users compared with nonusers but not when compared with each other. Thus, either all LLDs cause acute memory loss regardless of drug class or the association is the result of detection bias rather than a causal association.
Introduction
ABSTRACT | INTRODUCTION | METHODS | RESULTS | DISCUSSION | CONCLUSIONS | ARTICLE INFORMATION | REFERENCES

Although acute memory loss associated with the use of statins has been described in case reports and case series1- 8 as well as studies,9- 11 findings have been inconsistent, and studies of long-term use of statins have found either improved memory or no effect.12- 14 Mechanisms have been postulated both for impairment and improvement of memory with statin therapy. β-Amyloid plaques in the brain are thought to be related to dementia resulting from cholesterol buildup,2,15- 20 and the role of statins in interrupting deposition of plaques might delay the development of dementia.2,21,22 The lipophilicity of simvastatin and atorvastatin calcium that allows them to cross the blood-brain barrier could either confer protection2,20 or adversely affect memory if statins interfere with myelin production in the brain.2,23,24 King et al2 suggested that inhibition of myelin production could explain memory recovery after discontinuation of statin use because myelin stores can be replenished.
CNS Drugs. 2014 Mar;28(3):249-72. doi: 10.1007/s40263-013-0135-1.
Neuropsychiatric adverse events associated with statins: epidemiology, pathophysiology, prevention and management.
Tuccori M1, Montagnani S, Mantarro S, Capogrosso-Sansone A, Ruggiero E, Saporiti A, Antonioli L, Fornai M, Blandizzi C.

Statins, or 3-hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitors, such as lovastatin, atorvastatin, simvastatin, pravastatin, fluvastatin, rosuvastatin and pitavastatin, are cholesterol-lowering drugs used in clinical practice to prevent coronary heart disease. These drugs are generally well tolerated and have been rarely associated with severe adverse effects (e.g. rhabdomyolysis). Over the years, case series and data from national registries of spontaneous adverse drug reaction reports have demonstrated the occurrence of neuropsychiatric reactions associated with statin treatment. They include behavioural alterations (severe irritability, homicidal impulses, threats to others, road rage, depression and violence, paranoia, alienation, antisocial behaviour); cognitive and memory impairments; sleep disturbance (frequent awakenings, shorter sleep duration, early morning awakenings, nightmares, sleepwalking, night terrors); and sexual dysfunction (impotence and decreased libido). Studies designed to investigate specific neuropsychiatric endpoints have yielded conflicting results. Several mechanisms, mainly related to inhibition of cholesterol biosynthesis, have been proposed to explain the detrimental effects of statins on the central nervous system. Approaches to prevent and manage such adverse effects may include drug discontinuation and introduction of dietary restrictions; maintenance of statin treatment for some weeks with close patient monitoring; switching to a different statin; dose reduction; use of ω-3 fatty acids or coenzyme Q10 supplements; and treatment with psychotropic drugs. The available information suggests that neuropsychiatric effects associated with statins are rare events that likely occur in sensitive patients. Additional data are required, and further clinical studies are needed.
Biol Psychiatry. 1994 Apr 15;35(8):575-7.
Associations of cholesterol lowering by statins with anger and hostility in hypercholesterolemic men.
Strandberg TE1, Räikkönen K, Partinen M, Pihl S, Vanhanen H, Miettinen TA.
Am J Geriatr Pharmacother. 2008 Mar;6(1):28-32. doi:

Eur J Cardiovasc Nurs. 2012 Mar;11(1):85-96. doi: 10.1016/j.ejcnurse.2010.08.008.
The effects of statins on mood: a review of the literature.
While A1, Keen L.

To investigate the association between hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) and mood disturbance.
BACKGROUND:
The confirmation that high serum cholesterol levels increase the risk of coronary heart disease has resulted in statins becoming the most widely prescribed drugs in the treatment of hypercholesterolaemia. However, a positive relationship between low serum cholesterol levels and increased non-illness mortality from accidents and suicide has been reported.
METHOD:
Eight papers reporting the effect of statins on one or more of six mood states: depression, anxiety, anger, hostility, fatigue, confusion and vigour in adults older than 18 years were identified from a search of Cinahl, Medline and Cochrane electronic databases. The review focused on studies where the outcome of interest was self-reported mood disturbance as non-illness mortality is problematic.
KEY FINDINGS:
Three papers reported some evidence of a positive association with depression, whilst another reported a decreased incidence of depression and the remainder reported no association. Of the six papers which studied anxiety, only one reported a statistically significant decrease in the incidence of anxiety. Two out of six papers reported increased aggression with statin usage, with one study further indicating a stronger effect with lypophylic statins. In contrast one paper reported an outcome of decreased hostility.
CONCLUSION:
This review found conflicting evidence of a relationship between statins and mood.

10.1016/j.amjopharm.2008.03.001.
Behavioral changes with paranoia in an elderly woman taking atorvastatin.
Peters JT1, Garwood CL, Lepczyk M.

BACKGROUND:
There have been a number of published reports of central nervous system (CNS) adverse effects with statins.
CASE SUMMARY:
A 79-year-old woman developed paranoia, anxiety, and behavioral changes approximately 2.5 weeks after starting atorvastatin 10 mg/d. The patient had no other medication changes at this time. After 2 months of therapy, the patient discontinued atorvastatin, and her symptoms fully resolved after 4 days.
CONCLUSIONS:
This is the first case report, to our knowledge, describing paranoia as one of the symptoms associated with statin therapy. Our report suggests an adverse reaction due to the initiation of atorvastatin via the temporal relationship between the start of atorvastatin and symptom onset, as well as termination of therapy and subsequent symptom disappearance. Use of the Naranjo adverse drug reaction probability scale to assess causality revealed a “probable” association (score, 5) for this adverse event.

Lowering cholesterol concentrations and mortality: a quantitative review of primary prevention trials.
M F Muldoon, S B Manuck, and K A Matthews

OBJECTIVE–To determine the effects of lowering cholesterol concentrations on total and cause specific mortality in randomised primary prevention trials. DESIGN–Qualitative (meta-analytic) evaluation of total mortality from coronary heart disease, cancer, and causes not related to illness in six primary prevention trials of cholesterol reduction (mean duration of treatment 4.8 years). PATIENTS–24,847 Male participants; mean age 47.5 years. MAIN OUTCOME MEASURES–Total and cause specific mortalities. RESULTS–Follow up periods totalled 119,000 person years, during which 1147 deaths occurred. Mortality from coronary heart disease tended to be lower in men receiving interventions to reduce cholesterol concentrations compared with mortality in control subjects (p = 0.06), although total mortality was not affected by treatment. No consistent relation was found between reduction of cholesterol concentrations and mortality from cancer, but there was a significant increase in deaths not related to illness (deaths from accidents, suicide, or violence) in groups receiving treatment to lower cholesterol concentrations relative to controls (p = 0.004). When drug trials were analysed separately the treatment was found to reduce mortality from coronary heart disease significantly (p = 0.04). CONCLUSIONS–The association between reduction of cholesterol concentrations and deaths not related to illness warrants further investigation. Additionally, the failure of cholesterol lowering to affect overall survival justifies a more cautious appraisal of the probable benefits of reducing cholesterol concentrations in the general population.

Serum cholesterol in antisocial personality.
Virkkunen M
Neuropsychobiology [1979, 5(1):27-30]
Serum cholesterol fasting concentrations were measured in 274 subjects with personality disorders, who had committed offences. Of these subjects, 139 were found to possess the antisocial personality (sociopathy or psychopathy). With standardized ages, the group of subjects with antisocial personality had a clearly lower mean level of serum cholesterol than the group with other personality disorders which was used as a control group. The use of a mean male population with standardized ages as a control group further emphasized the low values of the serum cholesterol of the antisocial personality group.
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Nat Rev Neurol. 2015 Apr;11(4):220-9. doi: 10.1038/nrneurol.2015.35. Epub 2015 Mar 24.
Statins, cognition, and dementia—systematic review and methodological commentary.
Power MC1, Weuve J2, Sharrett AR1, Blacker D3, Gottesman RF4.
Firm conclusions about whether mid-life or long-term statin use has an impact on cognitive decline and dementia remain elusive. Here, our objective was to systematically review, synthesize and critique the epidemiological literature that examines the relationship between statin use and cognition, so as to assess the current state of knowledge, identify gaps in our understanding, and make recommendations for future research. We summarize the findings of randomized controlled trials (RCTs) and observational studies, grouped according to study design. We discuss the methods for each, and consider likely sources of bias, such as reverse causation and confounding. Although observational studies that considered statin use at or near the time of dementia diagnosis suggest a protective effect of statins, these findings could be attributable to reverse causation. RCTs and well-conducted observational studies of baseline statin use and subsequent cognition over several years of follow-up do not support a causal preventative effect of late-life statin use on cognitive decline or dementia. Given that much of the human research on statins and cognition in the future will be observational, careful study design and analysis will be essential.

FDA Expands Advice on Statin Risks
The Food and Drug Administration (FDA) has important safety information on cholesterol-lowering medications.
FDA is advising consumers and health care professionals that:
Cognitive (brain-related) impairment, such as memory loss, forgetfulness and confusion, has been reported by some statin users.
People being treated with statins may have an increased risk of raised blood sugar levels and the development of Type 2 diabetes.
Reports of Memory Loss
FDA has been investigating reports of cognitive impairment from statin use for several years. The agency has reviewed databases that record reports of bad reactions to drugs and statin clinical trials that included assessments of cognitive function.
The reports about memory loss, forgetfulness and confusion span all statin products and all age groups. Egan says these experiences are rare but that those affected often report feeling “fuzzy” or unfocused in their thinking.
In general, the symptoms were not serious and were reversible within a few weeks after the patient stopped using the statin. Some people affected in this way had been taking the medicine for a day; others had been taking it for years.
What should patients do if they fear that statin use could be clouding their thinking? “Talk to your health care professional,” Egan says. “Don’t stop taking the medication; the consequences to your heart could be far greater.”

Pharmazie. 2014 Jun;69(6):448-54.
Statins in nervous system-associated diseases: angels or devils?
Lei Q, Peng WN, You H, Hu ZP, Lu W.
Abstract
Statins are commonly prescribed lipid-lowering medications that significantly reduce the risk of cardiovascular events. In addition to their ability to lower cholesterol by affecting the rate-limiting step in cholesterol biosynthesis, statins also have anti-inflammatory, immunomodulatory, antioxidant, antiapoptotic, and antiplatelet effects. Because of these pleiotropic abilities, statins may have some beneficial effects on neurologic diseases, including cerebrovascular disease, neurodegenerative disease, multiple sclerosis, and brain tumors. Although statins are a well-tolerated class of drugs, they also have potential adverse effects (AEs). A growing body of evidence indicates that statins may have potential negative effects on nervous system-associated diseases, including myopathies, peripheral neuropathy, intracerebral hemorrhage (ICH), and other diseases of the central nervous system (e.g., cognitive impairment, depression, sleep disorders, nightmare, and headache). Clinicians, especially neurologists, should be aware of the potential risk of neuropathy in patients who take statins.

Pharmacotherapy. 2003 Jul;23(7):871-80.
Statin-associated memory loss: analysis of 60 case reports and review of the literature.
Wagstaff LR1, Mitton MW, Arvik BM, Doraiswamy PM.
To review case reports of statin-associated memory loss as well as the available published evidence for and against such a link.
METHODS:
We searched the MedWatch drug surveillance system of the Food and Drug Administration (FDA) from November 1997-February 2002 for reports of statin-associated memory loss. We also reviewed the published literature (using MEDLINE) and prescribing information for these drugs.
RESULTS:
Of the 60 patients identified who had memory loss associated with statins, 36 received simvastatin, 23 atorvastatin, and 1 pravastatin. About 50% of the patients noted cognitive adverse effects within 2 months of therapy. Fourteen (56%) of 25 patients noted improvement when the statin was discontinued. Memory loss recurred in four patients who were rechallenged with the drug. None of the 60 reported cognitive test results. Two placebo-controlled trials found no benefits for statins on cognition or disability. One randomized controlled trial of simvastatin found no effects on cerebrospinal amyloid levels. In one small, randomized study, patients receiving statins showed a trend toward lower cognitive performance than those receiving placebo. Five observational studies found a lower risk of dementia among patients receiving statins.
CONCLUSION:
Current literature is conflicting with regard to the effects of statins on memory loss. Experimental studies support links between cholesterol intake and amyloid synthesis; observational studies indicate that patients receiving statins have a reduced risk of dementia. However, available prospective studies show no cognitive or antiamyloid benefits for any statin. In addition, case reports raise the possibility that statins, in rare cases, may be associated with cognitive impairment, though causality is not certain.
BMJ Case Rep. 2009;2009. pii: bcr06.2008.0033. doi: 10.1136/bcr.06.2008.0033. Epub 2009 Feb 26.
Transient global amnesia associated with statin intake.
Healy D1, Morgan R, Chinnaswamy S.
A 57-year-old man treated with statins developed a range of amnestic features that led to concerns he might be suicidal; however, he did not appear to have depression. His problems began after starting rosuvastatin and cleared on discontinuation.

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