Neuropsychiatric Adverse Events Associated with Statins: Epidemiology, Pathophysiology, Prevention and Management

Abstract

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.

PCSK9 Inhibitors and Neurocognitive Adverse Events: Exploring the FDA Directive and a Proposal for N-of-1 Trials

“…Since 2012, systematic reviews [5,[29][30][31] and narrative reviews [32][33][34][35] have repeatedly reported a lack of conclusive evidence that statins cause cognitive impairment. A Cochrane review in 2013 found that a mean reduction in LDL-C by 22 % was not associated with worsening of cognitive function [36].…”

Toward Omics-Based, Systems Biomedicine, and Path and Drug Discovery Methodologies for Depression-Inflammation Research

“…However, there are conflicting data suggesting that statins may actually worsen depression [68]. Tuccori et al [69] 14 review that statins may cause many neuropsychiatric "side effects", including depression, irritability, paranoia, alienation, sleep disorders, neurocognitive impairments and muscle weakness. These negative effects of statins could possibly be driven through effects on other pathways, including lipid and serotonin metabolism, the key antioxidant coenzyme Q10 and induction of autoimmune responses [68][69][70].…”

“…Tuccori et al [69] 14 review that statins may cause many neuropsychiatric "side effects", including depression, irritability, paranoia, alienation, sleep disorders, neurocognitive impairments and muscle weakness. These negative effects of statins could possibly be driven through effects on other pathways, including lipid and serotonin metabolism, the key antioxidant coenzyme Q10 and induction of autoimmune responses [68][69][70]. Infliximab, a monoclonal antibody directed against TNF with anti-inflammatory and anti-oxidative effects, was recently shown to have antidepressive effects in patients with initially increased CRP levels [71].…”

Comparative evaluation of atorvastatin and simvastatin on critical fusion frequency in healthy volunteers

“…Tuccori et al [12] in their review has emphasized occurrence of neuropsychiatric reactions associated with statins like behavioral alterations such as severe irritability, homicidal impulses, threats to others, road rage, depression, violence, paranoia, alienation, antisocial behavior, cognitive and memory impairment, sleep disturbances, and sexual dysfunctions.…”