Neuropsychiatric adverse events associated with statins: epidemiology, pathophysiology, prevention and management.

CNS Drugs DOI 10.1007/s40263-013-0135-1

REVIEW ARTICLE

Neuropsychiatric Adverse Events Associated with Statins: Epidemiology, Pathophysiology, Prevention and Management Marco Tuccori • Sabrina Montagnani • Stefania Mantarro • Alice Capogrosso-Sansone • Elisa Ruggiero • Alessandra Saporiti Luca Antonioli • Matteo Fornai • Corrado Blandizzi

•

Ó Springer International Publishing Switzerland 2014

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

Electronic supplementary material The online version of this article (doi:10.1007/s40263-013-0135-1) contains supplementary material, which is available to authorized users. M. Tuccori (&) E. Ruggiero Tuscan Regional Centre of Pharmacovigilance, Florence, Italy e-mail: [email protected] M. Tuccori C. Blandizzi Unit of Adverse Drug Reaction Monitoring, University Hospital of Pisa, Via Roma, 55, 56126 Pisa, Italy S. Montagnani S. Mantarro A. Capogrosso-Sansone A. Saporiti L. Antonioli M. Fornai C. Blandizzi Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy E. Ruggiero Pharmaceutical Unit, University Hospital of Pisa, Pisa, Italy

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 x3 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.

1 Introduction Statins, or 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors (lovastatin, atorvastatin, simvastatin, pravastatin, fluvastatin, rosuvastatin and pitavastatin), are hypocholesterolaemic drugs with proven effectiveness in both primary and secondary prevention of coronary heart disease (CHD) [1]. Statins are generally well tolerated, although severe myopathy and rhabdomyolysis may rarely occur [2]. Over the years, there has been evidence suggesting that statins might provide benefits in several diseases of the central nervous system (CNS), particularly Alzheimer disease (AD) [3–5]. Human studies have suggested either protective actions or no beneficial effects of statins against AD or vascular dementia, mainly in patients with the apolipoprotein E (APOE) e4 genotype [4]. Other potential indications for statins in treatment and prevention of CNS disturbance include age-related cognitive impairment [6],

M. Tuccori et al.

depression [7], traumatic brain injury [8] and type 1 neurofibromatosis [9]. Although the outcomes of clinical studies investigating these potential therapeutic uses of statins have been conflicting, there is general agreement that statins can exert pharmacological effects on the CNS, which, in some instances, can be detrimental in nature [10]. One of the major clinical consequences of these adverse events could be discontinuation of statin treatment, which has been demonstrated to be essential especially in elderly people for secondary cardiovascular prevention [11, 12]. This review is aimed at describing the current knowledge of CNS adverse events associated with statin therapy, with a focus on those belonging to the system organ class ‘psychiatric disorders’, as defined by the Medical Dictionary of Regulatory Activities (MedDRA). The latter includes behavioural alterations and mood disorders, cognitive and memory impairments, sleep disturbance and sexual dysfunction. The clinical pharmacology of statins has been thoroughly discussed elsewhere and is not the primary focus of this article [13]. However, the consequences of genetic patterns on statin pharmacology and their drug–drug interactions are mentioned and discussed whenever there is evidence to suggest a potential implication for detrimental neuropsychiatric effects. The articles included in this review were randomized controlled trials (RCTs) and observational studies conducted on statins, in which specific neuropsychiatric endpoints were assessed. Case reports, where statins were the suspected causative drug of neuropsychiatric adverse events (AEs), have been also included. A literature search was performed using PubMed/MEDLINE, EMBASE and the Cochrane Library up to April 2013, without language restrictions. The key search terms for statins were ‘statin’ or ‘statins’ or ‘HMGCoA reductase inhibitors’ or ‘hydroxymethylglutaryl-CoA reductase inhibitors’ or ‘atorvastatin’ or ‘cerivastatin’ or ‘fluvastatin’ or ‘lovastatin’ or ‘pravastatin’ or ‘rosuvastatin’ or ‘simvastatin’ or ‘pitavastatin’. The following keywords, related to neuropsychiatric reactions, were selected: ‘neuropsychiatric reactions’ or ‘neuropsychiatric’ or ‘psychiatric reactions’ or ‘psychiatric’ or ‘psychiatric disorders’ or ‘psychiatric adverse effects’ or ‘psychiatric adverse drug reactions’ or ‘anxiety’ or ‘sleepiness’ or ‘insomnia’ or ‘agitation’ or ‘nervousness’ or ‘depression’ or ‘hallucination’ or ‘disorientation’ or ‘panic’ or ‘confusion’ or ‘obsessive–compulsive disorder’ or ‘panic’ or ‘delirium’ or ‘dementia’ or ‘amnesia’ or ‘cognition disorder’ or ‘attention deficit’ or ‘schizophrenia’ or ‘mood disorders’ or ‘personality disorders’ or ‘sexual and gender disorders’ or ‘sleep disorders’. Through this literature search, 1,234 articles were identified. The title and abstract of each article were reviewed independently by the authors in order to determine whether the article was relevant to the

review topic. Disagreements were resolved by discussion. For all potentially eligible references, the full text was obtained, and the studies were included if they met the prespecified inclusion criteria. The reference lists of retrieved articles were also reviewed to identify additional relevant studies. A specific analysis was conducted even on different hypolipidaemic/hypercholesterolaemic approaches, particularly on fibrates, ezetimibe, cholestyramine, nicotinic acid and omega-3 polyunsaturated fatty acids, with the aims of (1) attempting to generate hypotheses on the mechanisms underlying these effects; and (2) attempting to suggest alternative treatments when psychiatric adverse effects occur during statin treatment and discontinuation is required.

2 Epidemiology Initial case reports pointed out that statins could be associated with depressive symptoms, suicidal ideation and obsessive thoughts [14, 15]. More recently, data from national registries of spontaneous adverse drug reaction (ADR) reporting have highlighted the occurrence of a variety of psychiatric reactions in association with statin treatments. By November 2005, the New Zealand Centre for Adverse Reactions Monitoring (CARM) database had recorded 203 reports of psychiatric adverse events (classified using the World Health Organization Adverse Reaction Terminology [WHOART] dictionary) with statins (20.5 % of total ADR reports related to simvastatin, atorvastatin, fluvastatin and pravastatin); these reports included 67 ADRs classified as mood disorders, 30 events of cognitive impairment, 51 events of sleep disturbance, 14 perception disorders and 107 other reactions (asthenia, fatigue, lethargy, malaise, somnolence and tiredness) [10]. Likewise, a disproportion analysis, performed on the Italian Database of Spontaneous Adverse Drug Reaction Reporting up to June 2007, identified 60 reports of psychiatric disorders (classified on the basis of the MedDRA system organ class group) associated with statins (4.3 % of total ADRs were related to simvastatin, atorvastatin, fluvastatin, pravastatin, rosuvastatin and lovastatin) [16]. The association of statins with psychiatric events was assessed by the case/non-case methodology, calculating the ADR reporting odds ratio (ROR) as a measure of disproportionality. Cases were defined as patients with at least one reported ADR in the system organ class ‘psychiatric disorders’. The noncases comprised all patients who did not experience an ADR related to the system organ class ‘psychiatric disorders’. This analysis did not identify a significant risk of overall reporting of psychiatric events for statins as a whole class in comparison with all other drugs (adjusted ROR (AROR) 0.7, 95 % CI 0.6–1.0), although an increased

Neuropsychiatric Adverse Events Associated with Statins

reporting risk for insomnia was highlighted (AROR 3.3, 95 % CI 1.9–5.7) [16]. The data from New Zealand and Italy suggested different reporting rates for these adverse reactions. This can be explained by the two different dictionaries used for coding psychiatric disorders. Indeed, psychiatric conditions in the WHOART dictionary, used by Tatley and Savage [10], include asthenia, fatigue, malaise and tiredness, while in the MedDRA, these reactions are included in the system organ class ‘general condition and administration site disorders’. It should be noted that asthenia, fatigue, malaise and tiredness could be related to the well-known adverse effect of statins on muscles. For this reason, the MedDRA should be considered more suitable than the WHOART for classifying psychiatric adverse reactions. 2.1 Behavioural Alterations and Mood Disorders Clinical studies have evaluated the effects of statins on behaviour and mood by means of different endpoints. The main outcomes included aggression, anger, anxiety, depression, hostility, impulsivity and altered mood. Eight RCTs [17–23] evaluated behavioural and mood endpoints in patients treated with statins, with conflicting findings (Table 1). Five RCTs [17–21] observed neither detrimental nor beneficial psychiatric effects of statins. Hyyppa¨ et al. [22] reported a statistically significant risk of somatization, depression and self-reported aggressiveness in patients exposed to simvastatin in comparison with placebo. Morales et al. [23] observed that simvastatin does not appear to elicit depression, although it was associated with transient increments of probability that negative daily life events could impact negatively on mood. In the majority of the available observational studies [24–33] (Table 2), therapy with statins was not associated with an increased risk of behavioural or mood disorders [25–29, 32, 33]. Lindberg et al. [30] analyzed the prescription of cholesterol-lowering and antidepressant drugs, considering antidepressants as a proxy for depression. In this setting, only simvastatin showed a relative risk (RR) above the unit (1.59, 95 % CI 1.08–2.45), although none of the three major classes of cholesterol-lowering drugs (statins, fibrates and resins) were associated with a prescription asymmetry versus antidepressants, which might have indicated an increased risk of depression requiring treatment with antidepressants. It should be noted that symmetry analysis is sensitive to confounding by indication [30]. Ormiston et al. [24] described a modest increase in impulsivity after a short course (4 weeks) of atorvastatin/lovastatin therapy, which subsided over a longer course of therapy (52 weeks), suggesting that this alteration may occur early during treatment and be transient in nature.

Olson et al. [31] examined the association between lipid-lowering medications and aggressive attitude, hostility, cynicism and depression scores in women undergoing coronary angiography. Women on statins had higher aggressive behavioural scores than those not exposed to lipid-lowering medication (age-adjusted p = 0.03), and the use of statins was an independent predictor of aggressive behavioural scores in the regression analyses. Another study investigated the association of statins with depressive symptoms among community-living older persons. A subgroup analysis indicated that in women, at follow-up visits, the Geriatric Depression Scale score for statin users was significantly reduced as compared with the score in non-users (p = 0.02). In contrast, there was a trend for this score to be increased in male patients, albeit that the difference was not statistically significant [32]. Suicide is another psychiatric AE worthy of consideration. Suicide has been recorded during two large RCTs [34, 35] aimed at evaluating the efficacy and safety profile of statins. When the data from these studies were pooled, the frequency of suicide was comparable in patients receiving statins or placebo (0.13 vs 0.09 %, respectively). In particular, seven cases were observed in patients treated with statins (5 cases for simvastatin [35] and 2 cases for pravastatin [34] vs 5 cases in the placebo groups). These findings have fostered two nested case– control studies [26, 28], which reported no association between statins and an increased risk of suicide (Table 2). However, in the most recent study by Callreús et al. [28], only a small number of cases of suicide had a history of statin use (n = 3 past use; n = 4 current use). Therefore, risk attribution in this setting should be considered with caution [28]. Postoperative delirium is a peculiar psychiatric effect associated with statins [36–39]. The first investigators who observed an association between statins and an increased risk of postoperative delirium among elderly patients undergoing elective surgery (adjusted odds ratio [AOR] 1.28, 95 % CI 1.12–1.46, p \ 0.001) were Redelmeier and colleagues [36]. However, in their study, the true incidence of delirium may have been underestimated, since delirium coding in hospital discharge records was sometimes omitted [40]. Two subsequent observational studies found that statins exerted a protective effect on postoperative delirium after cardiovascular surgery, with odds ratios (ORs) of 0.56 (95 % CI 0.37–0.88, p = 0.011) [37] and 0.54 (95 % CI 0.3–0.84, p \ 0.01) [38], respectively. Furthermore, Katznelson et al. [38] observed that perioperative therapy with statins was associated with a significant decrease in delirium rates in patients aged C60 years (OR 0.61, 95 % CI 0.39–0.95, p = 0.03) but not in those aged \60 years (OR 0.78, 95 % CI 0.32–1.88, p = 0.57).

15 weeks

Placebo (N = 39)

Simvastatin up to 20 mg/day (N = 41)

12 weeks (crossover study)

Habitual diet ? placebo (N = 30)

Habitual diet ? simvastatin 20 mg/day (N = 30)

Dietary intervention ? placebo (N = 30)

Dietary intervention ? simvastatin 20 mg/day (N = 30)

208 weeks

Placebo (N = 571)

Pravastatin 40 mg/day (N = 559)

Placebo (N = 96) 24 weeks

Lovastatin 20 mg/day (N = 98)

24 weeks

Placebo (N = 142)



152 weeks

Placebo (N = 157)

Simvastatin 20 or 40 mg/day (N = 334)


Placebo (N = 25)

N = 80; age C65 (mean age 70); hypercholesterolaemic patients

N = 120; age 35–64 years; hypercholesterolaemic patients

N = 1,130; age 31–74 years; CHD, AMI

N = 209; age 24–60 years; hypercholesterolaemic patients

N = 431; age C65 years; MMSE score [24; LDL-C 159–221 mg/dL

N = 621; age 40–75 years; increased risk of CHD

HADS

N = 25; age 20–31.5 years (mean 23.8); healthy

Depressive symptoms: simvastatin: 4 (10.3 %); placebo: 1 (2.4 %) (exact p = 0.36) OR for bad mood on a day with a negative event: placebo: 4.66 (95 % CI 52.82–7.73); simvastatin: 9.72 (95 % CI 56.65–14.19)

CES-DS-Lawton Scale

Simvastatin increased somatization (p = 0.034), depression (p = 0.016) and self-reported aggressiveness (p = 0.049) compared with placebo

BSI, SSA

No differences in anxiety and depression (p = 0.23), anger (p = 0.44) and impulsiveness (p = 0.98) scores between treatment groups

GHQ, STAXI, BSI

No significant effect of lovastatin (p [ 0.2)

HDRS, NEO Depression, CMHS

Follow-up (6 months): no significant differences in mean change in CES-DS scores from baseline between treatment groups (p = 0.53)

CES-DS

Simvastatin did not adversely affect mood variations

MSQ

No cases of anxiety and depression

No significant differences between treatment groups

Outcome measure and main results

Subjects

AMI acute myocardial infarction, BSI Brief Symptom Inventory, CES-DS Center for Epidemiological Studies Depression Scale, CHD coronary heart disease, CI confidence interval, CMHS Cook–Medley Hostility Scale, GHQ General Health Questionnaire, HADS Hospital Anxiety Depression Scale, HDRS Hamilton Depression Rating Scale, LDL-C low-density lipoprotein cholesterol, MMSE Mini-Mental State Examination, MSQ Mood States Questionnaire, NEO Depression Depression scale of NEO Personality Inventory, OR odds ratio, SSA Strauss Scale of Aggression, STAXI Spielberger Anger Expression Scale

Morales et al. [23]

Hyyppa¨ et al. [22]

Stewart et al. [21]

Muldoon et al. [20]

Santanello et al. [19]

Wardle et al. [18]

Simvastatin 40 mg/day (N = 25)

Harrison and Ashton [17]


Treatment arms and duration

References

Table 1 Randomized controlled trials on behavioural impairment and mood disorders in subjects exposed to statins

M. Tuccori et al.

Feng et al. [32]

Olson et al. [31]

Lindberg and Hallas [30]

Prospective observational study

Singapore Longitudinal Ageing Studies cohort (Japan)

Retrospective analysis

Women’s Ischemia Syndrome Evaluation Study (USA)

Cohort study

Odense University Pharmacoepidemiological Database (Denmark)

Statins (not specified)

Statins or other (non-specified) cholesterol-lowering drugs

Simvastatin, lovastatin and pravastatin, fibrates, resins and other hypocholesterolaemic drugs


Rotterdam study database (the Netherlands)

Luijendijk et al. [29]

Prospective cohort study

Statins, any lipid-lowering drug, any calcium-channel blocker, bblocker, ACE inhibitor, angiotensin-receptor blocker

Lovastatin, atorvastatin, pravastatin, simvastatin, vs nonusers of statins

Statins or other lipid-lowering drugs

Danish Registry of Cause of Death and Odense University Pharmacoepidemiological Database (Denmark) Nested case–control study

Cohort study

Connecticut Veterans Longitudinal Cohort (USA)

Nested case–control study

General Practice Research Database (UK)

Simvastatin, atorvastatin, fluvastatin, lovastatin, cerivastatin and pravastatin or non-statin lipid-lowering agents

Drug(s)

Callreús et al. [28]

Agostini et al. [27]

Yang et al. [26]

Lown Cardiovascular Center (USA)

Young-Xu et al. [25]


Data source and study design

References

N = 1,803; age C55 years; community-living elderly

N = 954; age C18 years; women undergoing coronary angiography for suspected myocardial ischaemia

N = 184, patients receiving antidepressant therapy

N = 2,931; age C61 years; community-living elderly

N = 743 suicides, N = 14,860 controls

N = 756; age C65 years (mean age 74.5); communitydwelling veterans

Patients with suicidal behaviour (N = 105); nonsuicidal controls (N = 420)

Patients with a new diagnosis of depression (N = 458); non-depressed controls (N = 1,830)

N = 606; adult patients; CHD

Subjects

Table 2 Observational studies on behavioural impairment and mood disorders in patients exposed to statins

No depressive symptoms at follow-up vs baseline (p = 0.23); fewer depressive symptoms in female statin users (p = 0.02) and more depressive symptoms in male users (p = 0.04)

GDS symptom scores

Lipid-lowering medication may predispose to aggression (ageadjusted p = 0.002); women on statins (N = 152) had higher aggressive responding scores (age-adjusted p = 0.03)

CMHS, BDI

All statins: crude ARR 0.90, 95 % CI 0.68–1.22; simvastatin RR: 1.59 (95 % CI 1.08–2.45); other statins not significant

Co-prescription of cholesterol-lowering drugs and antidepressants

No relation to depression was observed with use of statins: model for individual risk factor: OR 1.28, 95 % CI 0.69–2.38, p = 0.441; multivariate model: OR 1.51, 95 % CI 0.73–3.15, p = 0.271

CES-DS, Depression (DSM-IV)

No drugs associated with increased risk of suicide: AOR for past use of statins 3.75, 95 % CI 0.96–14.57; AOR for current use 1.25, 95 % CI 0.42–3.76

Diagnosis of suicide

Chronic statin use does not adversely affect depressive symptoms (p = 0.49)

CES-DS

Current statin users vs non-users of antihyperlipidaemics: AOR for suicidal behaviour 0.5 (95 % CI 0.1–1.5)

Suicidal behaviour

Current statin users vs non-users of antihyperlipidaemics, AOR for depression 0.4 (95 % CI 0.2–0.9)

Depression (DSM-IV)

Statin users were less likely to have abnormal depression scores (OR 0.63, 95 % CI 0.43–0.93), abnormal anxiety scores (OR 0.69, 95 % CI 0.47–0.99) and abnormal hostility scores (OR 0.77, 95 % CI 0.58–0.93)

Kellner SQ

Outcome measures and main results


52 weeks

ACE angiotensin-converting enzyme, AOR adjusted odds ratio, ARR adjusted rate ratio, BDHI Buss–Durkee Hostility Inventory, BDI Beck Depression Inventory, BIS Barratt Impulsiveness Scale, CES-DS Center for Epidemiological Studies Depression Scale, CHD coronary heart disease, CI confidence interval, CMHS Cook–Medley Hostility Scale, DSM-IV Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, GDS Geriatric Depression Scale, Kellner SQ Kellner Symptom Questionnaire, OR odds ratio, PHQ Patient Health Questionnaire, ROR reporting odds ratio, RR relative risk

Decreased risk of depressive symptoms in statin users at 6-year follow-up (crude OR 0.68, 95 % CI 0.50–0.93, p = 0.02) Prospective cohort study

Clinics in the San Francisco Bay Area (USA) Otte et al. [33]

Case series

Atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin

N = 965; mean age *66 years; stable CHD

Week 4: mild increase in impulsivity (p \ 0.05) (9/12 patients); ratings of depression and hostility did not change significantly; week 52: mean impulsivity ratings returned to near baseline (p = 0.75); hostility ratings did not change significantly compared with baseline; depression ratings mildly but significantly improved as compared with baseline (p \ 0.05) PHQ, Depression (DSM-IV)

BDI, BDHI, BIS

N = 12; age 33–88 years (mean age 55); severe hypercholesterolaemia Atorvastatin 10–20 mg/day (N = 9) or lovastatin 20–40 mg/ day (N = 3) UC, San Francisco, Medical Center Lipid Clinic (USA) Ormiston et al. [24]

Drug(s) Data source and study design References

Table 2 continued

Subjects


M. Tuccori et al.

2.2 Cognitive Impairment Cognitive impairment in patients exposed to statins has emerged mainly in descriptive studies [12, 49]. Trottier [41] described 19 reports of amnesia potentially associated with statins, collected in the Health Canada database. Evans and colleagues [42] reported 171 cases of memory impairment or other cognitive disturbance associated with statins (p \ 0.00001) during the University of California San Diego (UCSD) Statin Effects Study [43]. Several studies have been performed to investigate possible correlations between statin treatments and changes in cognitive function. However, a large number of different tests have been used to evaluate neurocognitive parameters, and therefore comparisons among the heterogeneous results generated by these studies are very difficult. To the best of our knowledge, 15 RCTs [9, 12, 17, 19, 20, 44–53] (Table 3) with specific cognitive endpoints in healthy volunteers or hypercholesterolaemic patients receiving statins have been performed; the majority of those trials found no significant differences between statins and placebo in the scores of the different cognitive scales that were employed [9, 12, 17, 19, 44, 45, 47–49, 52, 53]; other studies showed a cognitive improvement related to statin treatment [20, 46, 51]. Only one study, performed in hypercholesterolaemic patients, reported cognitive impairment associated with simvastatin [50]. With regard to the available observational studies [6, 27, 54–66], 15 did not detect any change in cognition with statin use [6, 55, 59, 62, 64, 66] or any potential protective or beneficial effect of statins [27, 54, 56–58, 60, 61, 63, 65] (Table 4). Among those studies, three investigated dementia as a specific endpoint and concluded that statin use was associated with a lower prevalence of the disease [54, 56, 57]. Of note, advanced age and cardiovascular diseases may represent important confounding factors to be considered when investigating cognitive impairment, since statins are commonly used in elderly people and patients with cardiovascular problems. According to current evidence, these categories of patients do not display a particular risk of developing cognitive impairment when exposed to statins. Interestingly, Rockwood and colleagues [57] identified a lower prevalence of statin use in patients with dementia aged B80 years but not in those aged [80 years. 2.3 Sleep Disturbance Schaefer [67] was the first to observe that 9 (17.6 %) of 51 patients prescribed lovastatin experienced a reduction of 1 to 3 h in sleep time, as compared with a lack of sleep alterations in 33 patients receiving pravastatin. Black et al. [68] then assessed the prevalence of sleep disturbance in

Neuropsychiatric Adverse Events Associated with Statins Table 3 Randomized controlled trials on cognitive impairment in patients exposed to statins References


Subjects


Krab et al. [9]

Simvastatin (N = 31)

N = 62 children; age 8–16 years; Neurofibromatosis type I

CF, PA, mb-ADC, CT

N = 25; age 20–31.5 years (mean 23.8); healthy

DSST

N = 431; age C65 years; MMSE score [24, LDL-C 159–221 mg/dL

DSST

N = 209; age 24–60 years (mean 46); healthy adults with LDL-C C160 mg/dL

DV, LR, DS, RW, GP, EM, DSST, SI, T-MT, AL, COWA, DSR, VR, CF

Placebo (N = 31) 12 weeks Harrison and Ashton [17]

Simvastatin 40 mg/day (N = 25) Pravastatin 40 mg/day (N = 25)

No significant differences between simvastatin and placebo for all cognitive measures No significant differences between treatment group for cognitive performance

Placebo (N = 25) 4 weeks (crossover study) Santanello et al. [19]

Lovastatin 20 mg/day (N = 144) Lovastatin 40 mg/day (N = 145)

Follow up (6 months): no difference in mean change of scores from baseline between treatment groups (p = 0.66)

Placebo (N = 142) 24 weeks Muldoon et al. [20]

Lovastatin 20 mg/day (N = 98) Placebo (N = 96) 24 weeks

Kostis et al. [44]

Lovastatin 40 mg/day (N = 22) Pravastatin 40 mg/day (N = 22)

N = 22; age 36–65 years; hypercholesterolaemic men

Lovastatin improved cognition only in memory recall (p = 0.03); lovastatin did not cause any decline in cognition RT, RALT, T-MT, EFT, BVRT, VFT No significant effects of lovastatin or pravastatin on cognitive performance vs placebo

Placebo (N = 22) 6 weeks (crossover study) Cutler et al. [45]

Simvastatin 20 mg/day (N = 24) Pravastatin 40 mg/day (N = 24)

N = 36; age 40–60 years (mean 51); hypercholesterolaemic patients

DSST, VAS, AV, SRWR, FT, CRT, PMS

N = 36; age 40–60 years (mean 50.2); hypercholesterolaemic patients

DSST, VAS, CRT, AV, SRWR, FT

N = 80; age B59 years; hypercholesterolaemic patients

Cognitive function test

N = 30; age 45–75 years; diabetic dyslipidaemia

AVMT, orientation, attention, PS, EF

N = 5,804; age 70–82 years; CVD or existing risk factors

MMSE, 100-ISC-WT, L-DCT, 15-PLT

No significant effects of simvastatin vs pravastatin on cognitive measures; treatments did not differ significantly from placebo

Placebo (N = 24) 4 weeks (crossover study) Gengo et al. [46]

Lovastatin 40 mg/day (N = 24) Pravastatin 40 mg/day (N = 24) Placebo (N = 24)

No differences in cognitive parameters with the exception of DSST, for which both statins were better than placebo (p \ 0.05)

4 weeks (crossover study) Gibellato et al. [47]a

Lovastatin 40 mg/daya Pravastatin 40 mg/daya Placeboa 4 weeks

Berk-Planken et al. [48]

Atorvastatin 10 mg/day (N = 7) Atorvastatin 80 mg/day (N = 11) Placebo (N = 8)

Cognitive performance was not affected by either lovastatin or pravastatin and did not differ significantly from that in the placebo group Verbal memory did not improve with atorvastatin, while no effect was observed in the placebo group; atorvastatin did not exert significant cognitive effects

30 weeks Shepherd et al. [12]

Pravastatin 40 mg/day (N = 2,891) Placebo (N = 2,913) 164 weeks

No significant differences between the two groups in cognitive decline (p [ 0.19)

M. Tuccori et al. Table 3 continued References


Subjects


Collins et al. [49]

Simvastatin 40 mg/day (N = 10,269)

N = 20,536; age 40–80 years (mean *64); cerebrovascular disease, CHD, DM, HTN

TICS-m

N = 308; age 35–70 years (mean *53); hypercholesterolaemic patients

EM, DV, RW, GP, DSST, SI, T-MT, DS, CF, LR, MT, 4-WMT Simvastatin altered cognitive performance as compared with placebo (p = 0.008); performance improved on RW (p = 0.04) and EM (p = 0.02) tests in placebo-treated subjects but not in those receiving simvastatin; no significant difference on GP (p = 0.09), DV (p = 0.84), MT (p = 0.09); 4-WMT (p = 0.05)

N = 55; age C40 years (mean *56); CV indications, MMSE score [24

MMSE, DS, PT, T-MT, COWA, DSST, AV, DV

N = 1,016; age [20 years; LDL-C 115–190 mg/dL

RW, EM, DV, GP

N = 57; age 25–83 years (mean *61); CKD

NART, DSC, T-MT, 100-ISC-WT

Placebo (N = 10,267)

No significant differences between groups in the rate of cognitively impaired patients

272 weeks Muldoon et al. [50]

Simvastatin 10 mg/day (N = 96) Simvastatin 40 mg/day (N = 93) Placebo (N = 94) 24 weeks

Parale et al. [51]

Atorvastatin 10 mg/day (N = 49) Placebo (N = 48) 24 weeks

Golomb et al. [52]a

Pravastatin 40 mg/day (NA) Simvastatin 20 mg/day (NA) Placebo (NA) 24 weeks

Summers et al. [53]

Atorvastatin 10 mg/day (N = 30) Placebo (N = 27)

Beneficial effects of atorvastatin on cognitive function as measured in all tests (p \ 0.05) No significant impact on cognitive function (mental flexibility and memory) in either groups

Atorvastatin did not promote any decline in cognitive performance

12 weeks 4-WMT 4-Word Memory Test, 15-PLT 15-Picture Learning Test, 100-ISC-WT 100-Item Stroop Color-Word Test, AL associative learning, AV auditory vigilance, AVMT Auditory Verbal Memory Test, BVRT Benton Visual Retention Test, CF complex figure, CHD coronary heart disease, CKD chronic kidney disease, COWA controlled oral word association, CRT choice reaction time, CT Cancellation Test, CV cardiovascular, CVD cardiovascular disease, DM diabetes mellitus, DS digit span, DSC digit symbol coding, DSR digit symbol recall, DSST Digit Symbol Substitution Test, DV digit vigilance, EF executive functioning, EFT Embedded Figures Test, EM Elithorn mazes, FT finger tapping, GP grooved pegboard, HTN hypertension, L-DCT Letter-Digit Coding Test, LDL-C low-density lipoprotein cholesterol, LR letter rotation, mb-ADC mean-brainapparent diffusion coefficient, MMSE Mini-Mental State Examination, MT mirror tracing, NA not available, NART National Adult Reading Test, PA prism adaptation, PMS Profile of Mood States, PS psychomotor speed, PT Picture Test, RALT Rey Auditory Learning Test, RT reaction time, RW recurring words, SI stroop interference, SRWR Selective Reminding Word Recall, TICS-m Modified Telephone Interview for Cognitive Status, T-MT Trail-Making Test A/B, VAS Visual Analogue Scale, VFT Verbal Fluency Test, VR verbal recall a

Conference abstract

hyperlipidaemic patients taking lovastatin and found no differences in comparison with subjects treated with either diet alone, other statins or non-statin hypolipidaemic drugs. Two recent analyses of national databases of spontaneous ADR reporting have highlighted several cases of sleep disorders. Tatley and Savage [10] reported 51 events of sleep disturbance (including insomnia, nightmares and somnolence) among 203 reports of statin-related psychiatric adverse events received by the New Zealand regulatory agency. Tuccori et al. [16] identified 28 cases of statinrelated insomnia, with a significant AROR (3.3, 95 % CI 1.9–5.7) in comparison with the total number of events of insomnia reported for all other drugs in the Italian database of spontaneous ADR reporting.

Adverse drug reaction signals regarding statin-related insomnia, originating from case series and spontaneous reporting systems, have not been confirmed in the majority of the available clinical studies [17–19, 44, 69–76]. Indeed, the results of several RCTs [17–19, 44, 71–76] did not show any significant effects of statins on sleep performance when using different specific endpoints (Table 5). Even a large RCT (n = 8,245), the EXCEL study, evaluating the efficacy and tolerability of lovastatin without a specific endpoint for sleep performance, did not report a significant difference in the incidence of insomnia or other sleep alterations, when comparing the statin with placebo [77]. Only three studies found a correlation between sleep disturbance and statin treatments, two of which were

Neurological Disorders in Central Spain Study (Spain)

Benito-Leon et al. [6]

Li et al. [59]

Yaffe et al. [58]

Rockwood et al. [57]

Hajjar et al. [56]

Rodriguez et al. [55]

General Practice Research Database (UK)

Jick et al. [54]


Seattle area members of Group Health Cooperative (USA)

Cohort subanalysis

Heart and Estrogen/Progestin Replacement Study (USA)

Cohort and case–control study

Canadian Study of Health and Aging (Canada)

Case–control and retrospective cohort study

Richland Senior Primary Care Practice (USA)

Community-based cohort study

Monongahela Valley Independent Elders Survey (USA)

Nested case–control study

Connecticut Veterans Longitudinal Cohort (USA) Observational cohort study

Agostini et al. [27]

Cross-sectional cohort analysis


References

Atorvastatin, lovastatin, pravastatin and simvastatin

Simvastatin, atorvastatin, pravastatin, lovastatin and fluvastatin

LLA


LLA

Atorvastatin, cerivastatin, lovastatin, pravastatin and simvastatin

Lovastatin, atorvastatin, pravastatin and simvastatin vs non-users of statins

Atorvastatin, lovastatin, pravastatin, fluvastatin and simvastatin

Drug(s)

Table 4 Observational studies on cognitive impairment in patients exposed to statins

N = 2,356; age C65 years (mean 75.1); cognitively intact persons

N = 1,037; age \80 years; postmenopausal women, CHD

N = 1,315; age C65 years; dementia vs no dementia

N = 655; age 52–98 years (mean 78.7); dyslipidaemic patients or dementia; statin users vs nonusers

N = 845; mean age 80.5; dementia vs no dementia

N = 1,364; age 50–89 years; dementia vs no dementia

N = 756; age C65 years (mean age 74.5 years); ambulatory male patients

N = 5,278; age C65 years

Subjects

Non-significant association between statin use and reduced or increased risk of dementia (AHR 1.19, 95 % CI 0.82–1.75)

CASI

Modified MMSE score was higher in statin users than in non-users: p = 0.02; no association between changes in HDL-C and triglyceride levels and cognitive performance (OR 0.67, 95 % CI 0.42–1.05)

Modified MMSE

Patients B80 years: protective effects on dementia (OR 0.24, 95 % CI 0.07–0.80), patients [80 years: no protective effects on dementia (OR 0.43, 95 % CI 0.11–1.58)

MMSE

Patients on statins were less likely to have dementia (OR for composite dementia 0.23, 95 % CI 0.1–0.56, p = 0.001; OR for vascular dementia 0.25, 95 % CI 0.008–0.85, p = 0.027); MMSE score was better in patients treated with statins: OR for no change or improvement 2.81, 95 % CI 1.02–8.43, p = 0.045; CDT score was higher than that in the control group (p = 0.036)

MMSE, CDT

Patients with dementia were less likely to be taking statins, but this association was not significant (OR 0.54, 95 % CI 0.22–1.39, p = 0.179)

CDR

Users of statins had lower risk of developing dementia vs non-users (ARR 0.29, 95 % CI 0.13–0.63, p = 0.002)

Diagnosis of dementia

Outcome worsened in statin non-users (p = 0.08)

T-MT

No difference between statin users vs non-users (p = 0.062)

37-Item MMSE, T-MT, VF, SOT, SRT, WAT



Cache County (USA)

Multi-site cohort study

Electoral rolls of three French cities (France)

Prospective study of community-dwelling adults

Baltimore Longitudinal Study of Aging (USA)

Cross-sectional cohort analysis

Reasons for Geographic And Racial Differences in Stroke database (USA)

Prospective case–control study

National Health Service (Denmark)


Sacramento Area Latino Study on Aging (USA)

Prospective cross-sectional study

Atorvastatin, cerivastatin, lovastatin, pravastatin, fluvastatin and simvastatin

Lovastatin, fluvastatin, cerivastatin, atorvastatin, pravastatin and simvastatin

Atorvastatin, lovastatin and simvastatin

Atorvastatin, cerivastatin, lovastatin, pravastatin, fluvastatin, rosuvastatin and simvastatin

Atorvastatin, cerivastatin, lovastatin, pravastatin, fluvastatin, rosuvastatin and simvastatin

Lovastatin, fluvastatin, pravastatin and simvastatin


Drug(s)




N = 11,039 cases of dementia and 110,340 controls at risk of hospitalization for dementia



N = 478; test performed at ages of 11 and 80 years; no dementia

Subjects

For both genders, no association was found between cognitive decline or dementia incidence and statins (p [ 0.001)

VF, VM, T-MT, MMSE

Statin users had two- to three-fold lower risk of developing dementia (HR 0.41, 95 % CI 0.18–0.92)

DSM-IV, CDR, DQ, Petersen criteria

Cognitive impairment in 8.6 % of statin users vs 7.7 % of non-users (p = 0.014); after adjustment for confoundings, there was no association (OR 0.98, 95 % CI 0.87–1.10)

SIS

Reduced risk of hospitalization for dementia among statin users (AOR 0.67, 95 % CI 0.60–0.75)

No significant interactions between statin use and any of the covariates (diabetes, stroke, years of education, smoking status, presence of any APOE-e4 allele, modified MMSE score; AHR for use of statins and incidence of dementia/CIND for all covariates: 0.564 (95 % CI 0.365–0.872, p = 0.010) Diagnosis of dementia

DSM-IV, MMSE, SEVLT, SENAS, IQCODE

Statin use was inversely associated with onset of dementia (AOR 0.44, 95 % CI 0.17–0.94)

MMSE, IQCODE

Improvement of IQ score was observed among statin users at age 80 years than at baseline (at age 11 years); statins had a beneficial effect on lifelong cognitive changes (p = 0.017)

MHT


AHR adjusted hazard risk, AOR adjusted odds ratio, APOE apolipoprotein E, ARR adjusted relative risk, CASI Cognitive Abilities Screening Instrument, CDR Clinical Dementia Rating, CDT Clock Drowing Test, CHD coronary heart disease, CI confidence interval, CIND cognitive impairment without dementia, DSM-IV Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, DQ Dementia Questionnaire, HDL-C high-density lipoprotein cholesterol, HR hazard risk, IQ intelligence quotient, IQCODE Informant Questionnaire on Cognitive Decline in the Elderly, LLA lipid-lowering agents, MHT Moray House Test of Intelligence, MMSE Mini-Mental State Examination, OR odds ratio, SENAS Spanish English Neuropsychological Assessment Scales, SEVLT Spanish and English Verbal Learning Test, SIS Six-Item Screener, SOT Six Objects Test, SRT Story Recall Task, T-MT Trail-Making Test A/B, VF verbal fluency, VM visual memory, WAT Word Accentuation Test

Ancelin et al. [66]

Beydoun et al. [65]

Glasser et al. [64]

Horsdal et al. [63]

Cramer et al. [62]

Zandi et al. [61]

Scottish Mental Health Survey (1932) (UK)

Starr et al. [60]

Retrospective cohort analysis


References

Table 4 continued

M. Tuccori et al.

Roth et al. [71]

Vgontzas et al. [70]

Barth, et al. [69]

Kostis et al. [44]

Santanello et al. [19]

Wardle et al. [18]


Harrison and Ashton [17]

3 weeks

Placebo (N = 20)



Placebo (N = 12) 4 nights at baseline and 4 at withdrawal; 2 weeks



52 weeks

Colestipol 15 g/day (N = 15)



Placebo (N = 22)



24 weeks

Placebo (N = 142)



152 weeks

Placebo (N = 207)

Simvastatin 20 or 40 mg/day (N = 414)


Placebo (N = 25)



References

N = 59; age 18–38 years (mean 25.8); healthy men

N = 12; mean age *28 years; healthy

N = 30; men with hypercholesterolaemia and CHD. No history of sleep problems

N = 22; age 36–65 years; men with hypercholesterolaemia

N = 431; age C65 years; MMSE score [24, LDL-C 159–221 mg/dL

N = 621; age 40–75 years (mean *63); increased risk of CHD

Leeds Sleep Questionnaire

N = 25; age 20-31.5 years (mean 23.8); healthy

Neither pravastatin nor lovastatin significantly affected nocturnal sleep or daytime sleepiness in this study population; the responses to subjective sleep questionnaires did not change significantly from baseline in the pravastatin-treated subjects; lovastatin-treated subjects reported a significant increase in the number of awakenings (p \ 0.05) and a significant decrease in sleep quality (p \ 0.01); placebo recipients reported a decrease in sleep quality (p \ 0.001).

Sleep latency, stage 1 sleep, slow-wave sleep, total sleep time, WTASO, number of sleep arousals, sleep time, sleep quality and MSLT score

Lovastatin did not affect sleep initially (nights 5 through 7) but, with continued administration (nights 16 through 18), it increased awakening time after sleep onset and stage 1 sleep compared with baseline (p \ 0.05); pravastatin was not associated with sleep disturbance (initially or with continued use)

Sleep latency, WTASO, TWT, total number of awakenings, sleep time, sleep stages

Patients taking simvastatin had shorter sleep (p \ 0.01) vs matched controls taking colestipol (early awakening)

Duration of sleep

Compared with placebo, no significant effects of lovastatin or pravastatin on sleep measures

Total sleep time, time in each sleep stage, sleep efficiency, sleep latency, REM density, REM activity and number of arousals

Follow up (6 months): no difference in mean change scores from baseline between treatment groups on sleep (p = 0.93)

SBS

No evidence of simvastatin association with any sleep disturbance (insomnia: difficulty getting to sleep, disturbed, early waking); insomnia occurred in 165 patients (49 %) treated with simvastatin vs 84 patients (54 %) treated with placebo

Incidence of insomnia

Drugs did not exert significant effects on sleep as compared with placebo; on the sleep measure, subjects reported significantly greater difficulty in getting to sleep while on simvastatin (p = 0.05) than on pravastatin, but neither score differed from placebo


Subjects

Table 5 Randomized controlled trials on sleep impairment in patients exposed to statins


88 weeks

Placebo (N = 207)




Placebo (N = 16)



18 weeks

Pravastatin 10, 20, 40 mg/day (N = 333)

Lovastatin 20, 40, 80 mg/day (N = 339)

18 weeks

Pravastatin 10, 20, 40 mg/day (N = 275)

Simvastatin 10, 20, 40 mg/day (N = 275)


Placebo (N = 16)

N = 621; age 40–75 years; CHD

Sleep efficiency, number of awakenings, total sleep time, total wake time, wake time during sleep, entries to wake, entries to stage 1, latency to stage 1 sleep, latency to REM

N = 24; age 34–70 years (mean 55); men with primary hypercholesterolaemia

No adverse effects of prolonged treatment with simvastatin on systematically sought measures of sleep disturbance (insomnia: difficulty getting to sleep, disturbed sleep, early waking; fatigue, excess sleepiness, vivid dreams/ nightmares, prostatic symptoms, sleep duration)

Jenkins total sleep score

Neither lovastatin nor pravastatin caused substantial subjective or objective changes in sleep quality

Jenkins total sleep score Lovastatin produced no change (p \ 0.2) from baseline in sleep scores at any timepoint; pravastatin produced significant changes (p \ 0.01) from baseline in sleep scores at weeks 12 and 18; difference between groups at week 18 only (p = 0.02); no differences in the incidence of insomnia between pravastatin (1.2 %) and lovastatin (0.9 %)

1 case of sleep disturbance (0.4 %) in simvastatin group, 4 cases (1.5 %) in pravastatin group; decrease in sleep score at week 6 (p = 0.075) for simvastatin and at weeks 12 (p \ 0.05) and 18 (p \ 0.01) for pravastatin; no significant differences between groups in changes in total sleep score

Jenkins total sleep score

No significant differences between pravastatin, simvastatin and placebo, except in terms of entries and latency to stage 1 sleep; number of entries to stage 1 sleep significantly greater for simvastatin than for pravastatin or placebo (p \ 0.05); latency to stage 1 sleep prolonged in pravastatin group (p \ 0.05) vs placebo

Number of awakenings, latency to stage 1 sleep, sleep efficiency, percentages of stage 1 and REM sleep, entries to stage 1 and wake time during sleep, latencies to other sleep stages, total wake and total sleep times during recording, wake time after sleep


N = 672; mean age 54 years; hypercholesterolaemia

N = 550; age 18–71 years (mean age 52.5); primary hypercholesterolaemia, patients on a lipid-lowering diet

N = 24; age 36–70 years (mean 52.9); men with primary moderate hypercholesterolaemia

Subjects

CHD coronary heart disease, LDL-C low-density lipoprotein cholesterol, MMSE Mini-Mental State Examination, MSLT Multiple Sleep Latency Test, REM rapid eye movement, SBS Sleep Behaviour Scale, TWT total wake time, WTASO wake time after sleep onset

Keech et al. [76]

Partinen et al. [75]

Lovastatin Pravastatin Study Group [74]

Simvastatin Pravastatin Study Group [73]


Eckerna¨s et al. [72]



References

Table 5 continued

M. Tuccori et al.


conducted in healthy subjects treated with pravastatin or lovastatin [70, 71], and one of which was conducted in men with hypercholesterolaemia and CHD treated with simvastatin [69]. Vgontzas et al. [70] observed that pravastatin was not associated with any sleep disturbance. Nevertheless, continued administration of lovastatin affected the time elapsing between sleep onset and awakening. These results have been confirmed by Roth et al. [71], who described a significant increase in the number of awakenings (p \ 0.05) in subjects receiving lovastatin. Likewise, simvastatin was associated with repeated sleep interruptions (p \ 0.01) [69]. 2.4 Sexual Dysfunction Although sexual dysfunction may have a different origin from psychiatric dysfunction, both the MedDRA and the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition [78], have classified this dysfunction as being psychiatric in nature. Cases of impotence and decreased libido have been associated with statin use [79, 80]. It should be noted that the majority of studies evaluating specific endpoints of sexual dysfunction in patients receiving statins have been specifically focused on erectile dysfunction. Signals of erectile dysfunction in patients exposed to statins [81–83] have been reported by three separate analyses of national pharmacovigilance databases. Boyd [81] described 42 cases of erectile dysfunction specifically associated with simvastatin and recorded in the Australian Adverse Drug Reactions Advisory Committee (ADRAC) database (information about other statins was not reported). Later, a series of 38 cases of erectile dysfunction associated with use of statins (from 1989 to 2004) was reported in the Spanish ADR database [82]. Finally, a disproportion analysis in the French Pharmacovigilance Database showed a significantly higher number of reports of sexual dysfunction for statins versus other drugs (AROR 2.4, 95 % CI 1.8–3.3). After stratification, atorvastatin (AROR 3.4, 95 % CI 2.1–5.4), rosuvastatin (AROR 7.1, 95 % CI 2.6–19.4) and simvastatin (AROR 2.6, 95 % CI 1.6–4.1) displayed significant ARORs, while neither pravastatin (AROR 1.5, 95 % CI 0.8–2.8) nor fluvastatin (AROR 1.8, 95 % CI 0.4–7.4) showed a significant disproportion of sexual impairment [83]. Furthermore, Jackson [84] reported five cases of impotence, lethargy and inertia in men with CHD treated with simvastatin. On the basis of early reports of sexual disturbance, Pedersen [85] examined these adverse events during the Scandinavian Simvastatin Survival Study and found that simvastatin did not appear to cause impotence or other erectile dysfunction more frequently than placebo (RR 1.30, 95 % CI 0.80–2.12, p = 0.32) in men with CHD

(n = 3,617). In another crossover study, conducted by Kostis and colleagues [44], nocturnal penile tumescence was evaluated in men treated with lovastatin and pravastatin. The authors observed a significant increase in the duration of nocturnal tumescence after 2 weeks of treatment with both study drugs, but this effect was not significant after 6 weeks of treatment [44]. Among the three observational studies (Table 6), one estimated the risk of erectile dysfunction related to statins in patients with cardiovascular risk factors (OR 1.51, 95 % CI 1.26–1.80) [86]. In the second study, conducted in male patients with CHD, Kloner and colleagues [87] administered the validated Sexual Health Inventory for Men (SHIM) 5-item questionnaire and observed that 75 % of patients had some difficulty in achieving erections and 67 % had difficulty in maintaining an erection after penetration. Almost all of these patients were taking statins (92 %). In the third study, Solomon and colleagues [88] found a reduction of the International Index of Erectile Dysfunction (IIEF) score, indicating a significant worsening of erectile function with unspecified statin treatment. Three studies (one RCT and two observational studies) evaluated the effects of statins in patients with erectile dysfunction at baseline [89–91]. In one study [90], statin use was associated with a reduced testis volume and a higher prevalence of hypogonadism-related symptoms and signs. The other two studies assessed the effect of statin therapy on erectile dysfunction. Particularly in the study by Saltzman and colleagues [89], erectile function improved in men with hypercholesterolaemia treated with atorvastatin. However, in the RCT conducted by Mastalir and colleagues [91], no significant difference in penile erection after intake of simvastatin or placebo was observed.

3 Pathophysiology Proposed mechanisms underlying the adverse affects of statins on the CNS can be classified as primary (or direct) and secondary. The latter include psychiatric reactions that can be associated with statin effects on organs and tissues other than the CNS, with subsequent accumulation of toxic compounds. An example is the symptom of confusion associated with rhabdomyolysis and renal impairment [92]. The primary mechanisms are more complex and appear to be mainly dependent on inhibition of the cholesterol metabolic pathway. Cholesterol is a compound endowed with pivotal biological functions, which include (1) being a substrate for biosynthesis of steroid hormones (e.g. testosterone, oestrogen, cortisol and vitamin D) and bile acids; (2) biophysical properties of cell membranes; (3) formation and

Prospective observational study

Statins not specified

CHD coronary heart disease, CI confidence interval, ED erectile dysfunction, HR hazard ratio, IIEF International Index of Erectile Dysfunction, OR odds ratio, SHIM Sexual Health Inventory for Men

After starting statin therapy, 43/82 (52 %) experienced a significant reduction in the IIEF score, indicating a significant worsening of erectile function; 18/82 men (22 %) experienced new onset of ED

N = 82 men; mean age 61 ± 10 years; CHD; hypertension and hyperlipidaemia

IIEF

75 % of patients had some difficulty achieving erections and 67 % had difficulty maintaining an erection after penetration; 92 % of these patients were taking statins

SHIM 5-item questionnaire

N = 76 men; mean age 64 years; chronic stable CHD Statins, beta-blockers, diuretics Observational study

Cardiology and lipid clinics of two London teaching hospitals (UK) Solomon et al. [88]

Case–control study

SHIM 5-item questionnaire during routine outpatient cardiology visits (USA) Kloner et al. [87]

Higher ED rate in the group receiving hypolipidaemic drugs (12 vs 5.6 %, p = 0.0029); ED was associated with fibratederivative treatment (OR 1.46, 95 % CI 1.27–1.68) and statins (OR 1.51, 95 % CI 1.26–1.80)

ED

Cholestyramine, simvastatin, pravastatin, fenofibrate, aprofibrate, bezafibrate, gemfibrozil Hopital Pitie´-Salpe´trie`re database (France) Bruckert et al. [86]

N = 339 men; mean age 48 ± 9.5 years; cardiovascular risk factors

Drug(s) Data source and study design References

Table 6 Observational studies on sexual dysfunction in patients exposed to statins

Subjects


M. Tuccori et al.

maintenance of membrane lipid rafts (MLRs)—specialized membrane microdomains involved in several aspects of brain function, such as receptor expression and signalling, axon guidance, synaptic development and neurotransmission; (4) formation of myelin sheaths; and (5) transport of antioxidant compounds (e.g. vitamin E, carotenoids and coenzyme Q10) involved in energy production, cell function and defence against free radicals [93]. The brain is the most cholesterol-rich organ, with approximately 25 % of total body cholesterol content. The majority of cholesterol (70–90 %) in the CNS is embedded in myelin sheaths, which surround axons to ensure isolation and fast transmission of electrical signals. Unlike in other tissues, brain cholesterol is synthesized in situ, since plasma lipoproteins do not cross the blood–brain barrier. Therefore, CNS cholesterol homeostasis is regulated independently from that of cholesterol circulating in peripheral organs. Cholesterol biosynthesis is higher during myelination (at young ages) and undergoes a gradual reduction of about 90 % in adulthood. In fully mature brains, cholesterol biosynthesis occurs mainly in astrocytes, which, together with APOE and phospholipids, generate lipoproteins. Indeed, APOE acts as a ‘shuttle’ system to transport cholesterol from glial cells to neurons through a process mediated by a single or multiple adenosine triphosphate (ATP)-binding cassette transporters (e.g. ABCA1 and ABCG1). The homeostasis of brain cholesterol is ensured by at least two excretory pathways: one involving the formation of 24(S)-hydroxycholesterol and the other one being minimal excretion of APOE-bound cholesterol into the cerebrospinal fluid (CSF). Thus, on the basis of the above considerations, a deficiency or excess of cholesterol in the brain is expected to have relevant consequences [94, 95]. Early studies correlated depression [96–98], suicidal behaviour [98–104], impulsivity and aggression [105] with low serum cholesterol levels. Psychotropic drugs have also been shown to impair CNS cholesterol concentrations [106–108]. However, the majority of those studies were of low quality, due to the lack of control for confounding variables, such as age, gender, smoking habits, alcohol intake, physical activity and drug intake. Moreover, low serum cholesterol levels in these subjects could result from reduced food intake associated with several psychiatric conditions, even though some studies were able to control for confounding by the body mass index [104] or other markers of nutritional status [102, 103]. Statins comprise a family of drugs endowed with different chemical properties: simvastatin, lovastatin, atorvastatin, fluvastatin and pitavastatin are lipophilic compounds, while pravastatin and rosuvastatin are endowed with hydrophilic chemical structures [109]. Through inhibition of HMG-CoA reductase, statins block


conversion of HMG-CoA into mevalonate, which represents the first step in cholesterol biosynthesis. As a result of statin administration, low-density lipoprotein (LDL) cholesterol biosynthesis decreases in hepatocytes, and this effect translates into a reduction in cholesterol blood levels. Literature data concerning the effects of statins on the nervous system are often conflicting, likely as a consequence of the different experimental models and types of statin employed [109]. In a mouse brain model, reduced cholesterol levels have been detected following long-term treatment with simvastatin but not pravastatin [109]. In samples of the visual association cortex from patients with bipolar disorder, major depressive disorder or schizophrenia, reduced cholesterol levels have been found, as compared with controls [95]. In such patients, statins might worsen the background disorder, leading to cognitive impairment, agitation and sleep disturbance. A study evaluating changes in brain cholesterol metabolism, as documented by assays in the CSF before and after treatment with atorvastatin or simvastatin, showed a maximum decrease in lathosterol, cholesterol and 24(S)-hydroxycholesterol levels by 6–7 months, followed by a return to baseline after 15 months [110]. A possible explanation for this observation involves a compensatory increase in HMG-CoA reductase activity to restore brain cholesterol biosynthesis. Accordingly, the incidence of the psychiatric effects of statins can be higher during the initial period of treatment. On the basis of the available data, at least seven not mutually exclusive mechanisms can be proposed to explain the neuropsychiatric effects of statins, with an eighth one accounting specifically for sexual disorders (Fig. 1). The majority of these mechanisms depend on inhibition of HMG-CoA reductase, with a possible exception for two of them. The first mechanism deals with inhibition of biosynthesis of non-sterol isoprenoids, such as farnesyl-pyrophosphate (FPP) and geranyl-geranyl-pyrophosphate (GGPP), which are metabolic products generated by the mevalonate pathway and employed for protein prenylation. Prenylation is a posttranslational process affecting the functions of Ras, Rho and other small guanosine triphosphatase (GTPase) proteins [111]. Linking of isoprenoids to small G-proteins is crucial to ensure their proper translocation and anchoring to cell membranes, where they exert their regulatory actions. Small GTPases of the Rho family regulate the dynamics and stability of the microfilament system and can also influence the microtubular system organization of the cytoskeleton. In particular, Rho GTPase signalling is important for formation and structural remodelling of synapses, acting as a key regulator of neural plasticity associated with learning, memory and cognitive function [111]. In this context, statins can deplete isoprenoid formation, cause loss of GTPase membrane

binding and lead to its cytosolic accumulation [112, 113]. Moreover, lack of isoprenoids can promote neuronal cell death, as has been shown in cultured rat brain neurons [114, 115]. The second mechanism is associated with the impact of statins on oxidative stress and mitochondrial function. Statins have been shown to inhibit production of coenzyme Q10 via inhibition of mevalonate biosynthesis. Coenzyme Q10 is essential for proper mitochondrial function, cellular ATP production and antioxidant activity. Therefore, statins are thought to decrease coenzyme Q10 levels, leading to impaired mitochondrial functioning and increased oxidative stress. Through this mechanism, statins might exert indirect adverse effects on cognition [116]. The third mechanism is related to excess inhibition of cholesterol biosynthesis. Statins—mainly those endowed with lipophilic chemistry—can cross the blood–brain barrier and inhibit brain cholesterol biosynthesis, with possible consequences for synaptic cholesterol homeostasis and myelin formation. Inadequate myelin production results in demyelination of CNS fibres, possibly leading to memory loss [117]. In support of this mechanism, it is important to consider that most reports of memory loss and cognitive impairment have been associated with lipophilic statins. The fourth mechanism pertains to the key role of cholesterol as a component of cell membranes and, in particular, as an essential element of MLRs, which are pivotal for synaptic function [118]. Disruption or alterations of MLRs by statins can result in neurotoxic events, underscoring the importance of these membrane microdomains for proper nerve signalling [118–121]. Of note, MLRs regulate subcellular localization and function of certain membrane receptors and proteins involved in signal transduction, such as G-proteins. There is increasing evidence that the membrane localization of neurotransmitter receptors within MLRs can influence their function by affecting neurotransmitter binding, as well as receptor trafficking and clustering [122]. Indeed, cholesterol reduction has been found to impair synaptic vesicle exocytosis, thus affecting neuronal signalling in cultured neurons [123]. In vitro and in vivo studies in aged animals have also shown that the fatty acid content of MLRs, isolated from synaptic endings, has differential composition and selective localization of phosphatidylcholine-derived signalling [124]. According to these findings, cognitive function in the elderly might be more vulnerable to statin-associated changes in neuronal structure and function, with possible occurrence of delirium. Overall, the MLR perturbation mechanism could explain serotonin (5-HT) and dopamine neurotransmission impairments, which have been associated with chronic cholesterol depletion. Reduction of the 5-HT metabolite

M. Tuccori et al. Fig. 1 Proposed mechanisms of statin-associated neuropsychiatric adverse effects. The inhibition of hydroxyl-methyl-glutarylcoenzyme A (HMG-CoA) reductase by statins can lead to (1) a decrease in the synthesis of isoprenoid compounds (farnesyl-pyrophosphate [FPP] and geranyl-geranylpyrophosphate [GGPP]); and (2) reduced production of coenzyme Q10 (CoQ10) and cholesterol. The latter effect may result in (3) reduction of myelin formation; (4) alteration of membrane lipid rafts (MLRs) with detrimental consequent effects on neurotransmission, such as serotonin (5-HT) and dopamine (D); (5) reduction of neurosteroid biosynthesis; and (6) increased phosphorylation of tau-protein. Mechanisms independent of HMG-CoA reductase inhibition include (7) increased arachidonic acid (AA) release, with consequent alteration of the x6 to x3 polyunsaturated fatty acids ratio; and (8) peripheral inhibition of testosterone biosynthesis (sexual disorders) by inhibition of 17-ketosteroid (KS)-reductase and decrease in the availability of cholesterol. CoA coenzyme A, CNS central nervous system, GTPase guanosine triphosphatase, NFT neurofibrillary tangles

5-hydroxyindoleacetic acid (5-HIAA) in the CSF has repeatedly been associated with depression, suicidal behaviour and aggressive attitude [125]. It has been speculated that cholesterol reduction could contribute to serotonergic abnormalities in subjects who are vulnerable to development of psychiatric events by further exacerbating serotonergic deficiencies [99, 126, 127]. On this basis, several preclinical and clinical investigations have been performed to assess the impact of low cholesterol on serotonergic neurotransmission. In vitro studies have shown that the cholesterol content in neuronal membranes modulates presynaptic 5-HT transporters and postsynaptic signal transduction. Incubation of synaptosomal membranes from canine and bovine brains with cholesterol reduced the activity of membrane-bound adenylyl-cyclase

[128, 129]. Furthermore, increasing the cholesterol content of mouse and rat brain membranes resulted in an increase in [3H]-5-HT binding [130, 131]. Cynomolgus macaques that were fed a low-cholesterol diet showed lower CSF concentrations of 5-HIAA and a blunted prolactin response after stimulation with d-fenfluramine, as compared with controls on a high-cholesterol diet. Both of these outcomes are markers of low serotonin activity in the brain. Furthermore, monkeys fed with a low-cholesterol diet displayed more aggressive behaviour when involved in physical contact [132–134]. Early studies in humans suggested that low serum cholesterol levels can be associated with reduced serotonergic neurotransmission. In a cholesterol screening study among 30,359 men, lower plasma 5-HT concentrations were found in


untreated subjects with cholesterol concentrations below the 5th percentile [135]. In more recent cell culture studies, reduced activity of the 5-HT receptors 5-HT1A, 5-HT3 and 5-HT7 has been shown in the presence of reduced cholesterol levels [136–139]. Vevera et al. [140] reported that long-term therapy with simvastatin had different effects on 5-HT transmission than short-term (1to 2-month) treatment. In particular, a significant increase in platelet serotonin transporter activity was detected in patients only during the first month of simvastatin administration, suggesting that, through that period, some patients could be vulnerable to depression, violence or suicide. As far as dopamine neurotransmission is concerned, Wang et al. [141] observed that high doses of simvastatin upregulate dopamine D1 and D2 receptor expression in the rat prefrontal cortex, resulting in sedative or psychotropic effects. The fifth mechanism is linked to reduced synthesis of neurosteroids caused by low brain cholesterol levels, which may elicit depression [122]. Neurosteroids are potent neuromodulators, synthesized from cholesterol in the brain, where they contribute to neuroprotection, spinogenesis and synaptogenesis, as well as to modulation of neuronal excitability through their interaction with gamma-aminobutyric acid (GABA) receptors [142]. Accordingly, both in vivo and in vitro studies have shown that dysregulation of neurosteroid production plays a significant role in the pathophysiology of stress and stress-related psychiatric disorders, including anxiety, depression, aggressive behaviour and mood disorders [143]. The sixth mechanism implies that low neuronal cholesterol levels are involved in increased phosphorylation of tau-protein and cell death [144, 145]. Indeed, hyperphosphorylated tau-protein has a reduced binding capacity, with a consequent decrease in its microtubular-stabilizing properties, and may thus play an important role in formation of neurofibrillary tangles (NFTs) and axonal degeneration, leading to cognitive impairment, as occurs in patients affected by AD [144]. The seventh mechanism is independent from HMG-CoA reductase inhibition [146, 147] and involves statin-related enhancement of the release of arachidonic acid (AA), the main membrane omega (x)-6 fatty acid, which then inhibits the protective effects of x-3 fatty acids (eicosapentanoic acid [EPA] and docosaesaenoic acid [DHA]), since these compounds compete mutually through various mechanisms [148]. It has been demonstrated that depression severity correlates positively with the AA to EPA ratio in plasma and erythrocyte phospholipids [149]. An increase in the AA to EPA ratio can result from a statin-related AA increase [148]. On the other hand, low levels of x-3 polyunsaturated fatty acids have been linked to several psychiatric disorders, including depression, alterations of impulse control and

hostility [150]. Decreased intake of x-3 fatty acids correlates with increased rates of depression [151]. The mechanisms of sexual impairment associated with statins have been investigated in several studies, which suggested that such disturbance can result from a peripheral action more than a central one. Libido is related to serum testosterone levels [152]. In males, testosterone is produced mainly in the Leydig cells, where cholesterol is the main substrate. Leydig cells can uptake cholesterol from the blood via LDL receptors, but they are also capable of performing de novo cholesterol biosynthesis [153]. Statins may interfere with testosterone biosynthesis in two ways. First, by decreasing plasma LDL cholesterol levels, statins can decrease the total amount of cholesterol available for uptake by Leydig cells [154, 155], which makes these cells more dependent on de novo cholesterol biosynthesis (a HMG-CoA–dependent mechanism). Statins are rather liver selective but are found in small amounts also in the testes, where they can inhibit the de novo production of cholesterol and, consequently, of testosterone [156]. Second, high-dose simvastatin, and possibly other statins, directly suppress testosterone biosynthesis by inhibition of androstenedione conversion to testosterone by 17-ketosteroid-oxidoreductase (an HMG-CoA–independent mechanism) [157]. Two RCTs [22, 154] and one observational study [156] have examined the effects of statin treatment on hormonal levels. Jay and colleagues [154] observed that pravastatin did not interfere significantly with concentrations of adrenal steroid hormones in male and female subjects or with concentrations of gonadotrophin in male subjects. It should be noted that the control group enrolled in that study were treated with cholestyramine. To the best of our knowledge, that was the only study to have investigated steroid hormone levels in female patients receiving statins [154]. In contrast with the observations of Jay et al. [154], Hyyppa¨ and colleagues [22] reported that in men with hypercholesterolaemia, treatment with simvastatin lowered serum testosterone levels more than placebo (p = 0.0186). One observational study [156] assessed testicular function in hypercholesterolaemic male patients during prolonged simvastatin treatment. A significant decrease in free testosterone was observed in the sixth and twelfth months of the study period. However, free testosterone levels remained in the normal range, and no patient complained of symptoms related to gonadal function [156]. When considering different hypolipidaemic/hypercholesterolaemic approaches, current evidence does not provide useful information for generating hypotheses about pathogenic mechanisms underlying psychiatric events. A few case reports [15, 158–161] have described switching to different hypocholesterolaemic approaches in an attempt to resolve psychiatric conditions, with both positive [158–

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161] and negative outcomes [15]. Of note, the limited body of evidence on the putative psychiatric effects of non-statin hypocholesterolaemic medications can likely be explained as a consequence of their relatively lower usage in clinical practice, as compared with statins.

developing CNS adverse effects [79, 166], and they advised use of hydrophilic statins when these drugs must be administered concomitantly. Of course, these recommendations will need to be substantiated by future studies. 4.1 Behavioural Alterations and Mood Disorders

4 Prevention and Management Because of differences in clinical manifestations and potential pathogenic mechanisms of statin-associated psychiatric AEs, prevention and management can vary both across conditions and on an individual basis. Owing to the lack of specific studies, recommendations can be given only by reviewing the available case reports with a particular focus on treatments, outcomes, potential risk factors and drug–drug interactions. Over the period 1992–2012, at least 45 case reports of statin-associated psychiatric AEs (in 28 males; median age 54 years, range 10–79 years) were published [10, 15, 79, 80, 117, 158–174] (see the Electronic Supplementary Material). In those case reports, the median onset time for overall psychiatric events since the first statin administration was 41 days (range 4–420 days). In 42 cases (93 %) [10, 15, 79, 80, 117, 158–174], statin administration was discontinued, and symptom resolution occurred spontaneously in 32 cases (76 % of discontinuations) [10, 79, 80, 117, 158, 160–165, 168–174]. The median recovery time after statin discontinuation was 14 days (range 1–180 days) [10, 15, 79, 80, 117, 158–174]. Treatment with antidepressants or antipsychotic drugs was rarely required [162]. Usually, symptoms did not recur when a statin was switched to other hypocholesterolaemic/hypolipidaemic approaches (ezetimibe, unspecified dietary restrictions, or omega 3) [158– 161], although there were some exceptions [15]. Switching to a different statin [15, 79, 80, 117, 159, 163, 164, 166, 167, 169] was able to resolve symptoms both with [159, 163] and without [15, 80, 163, 164, 167] a washout period. Switching from a lipophilic statin to a hydrophilic statin [79, 80, 159, 163, 164, 166, 167] did not resolve symptoms [79, 159, 166]. The available case reports do not allow retrieval of information on the number of patients who remained definitively without hypocholesterolaemic medication or on what cardiovascular events occurred after statin discontinuation. As far as drug–drug interactions are concerned, concomitant use of beta-blockers (metoprolol, bisoprolol and atenolol) has been documented in some cases [79, 117, 166, 168, 170]. Because of their lipophilic nature, these drugs can cross the blood–brain barrier and cause CNS adverse effects [175]. Some authors have hypothesized that concomitant administration of beta-blockers with statins (especially lipophilic ones) would increase the risk of

Behavioural alterations and mood disorders (severe irritability, homicidal impulses, threats to others, road rage, generation of fear in family members, depression and violence, paranoia, alienation and refusal of participation in routine social activities) have been reported with use of all statins [10, 15, 117, 160, 162, 163, 165, 168, 169, 171– 174], mostly with simvastatin (n = 12) [10, 162, 168, 169, 171, 174] and atorvastatin (n = 9) [10, 117, 160, 165, 169, 172]. The median age of the patients was 58 years (range 32–79 years). The median time to onset was 49 days (range 1–420 days), and the median recovery period from statin discontinuation was 14 days (range 1–42 days). In the majority of cases, statin administration was discontinued [10, 117, 160, 162, 163, 165, 168, 169, 171–174] and symptom resolution occurred spontaneously [10, 117, 160, 165, 168, 169, 171–174]. Switching to a different hypocholesterolaemic approach (fibrates) or other statins may not resolve the ADR [169]. A history of psychiatric disorders or treatments with psychotropic medications was reported in some cases [10, 15, 162, 169, 173, 174]. There is evidence of a potential statin dose relationship with the development of these reactions [117, 165]. 4.2 Cognitive Impairment Cognitive impairment (significant impairment in short- and long-term memory, memory loss, confusion, problems in understanding simple text or when watching television, difficulty in concentrating or in remember names and words) has been reported for simvastatin, atorvastatin and rosuvastatin. The median age of the patients was 53 years (range 40–70 years). With regard to the adverse event, the median onset time from the first exposure to statins was 56 days (range 1–360 days), and the median recovery time was 17.5 days (range 1–42 days) from statin discontinuation or symptom onset. Discontinuation was usually associated with symptom resolution. [117, 158, 160, 161, 165, 168, 171, 173] 4.3 Sleep Disorders Sleep disturbance is characterized by frequent awakenings, shortened sleep duration and early morning awakenings. Sometimes, nightmares, sleepwalking and night terrors can occur [163]. Statins have been reported to elicit mostly nightmares, defined as a rapid eye movement phenomenon


associated with frequent, elaborate recall of frightening dreams perceived as threatening survival or security [159]. Sleep disorders associated with statin therapy have been reported for lovastatin, simvastatin and atorvastatin [159, 160, 163, 164, 166, 170]. The median age of the patients was 52 years (range 10–79 years). The median onset time was 28 days (range 5–90 days), and the median recovery period was 30 days (range 2–180 days). Adverse reaction recovery was documented both with statin discontinuation [160, 163, 164, 170] and with switching to a different statin [163, 164]. 4.4 Sexual Disturbance Sexual disturbance is characterized by impotence and decreased libido. It is usually related to low serum testosterone levels, leading to a decrease in male libido [79, 80]. Sexual disorders have occurred with all statins [79, 80, 160]. The median age of the patients was 53.5 years (range 40–67 years). The median onset time was 42 days (range 4–120 days), and the median recovery time was 14 days (range 5–35 days). Recovery with statin discontinuation or switching to a different statin has been reported [79, 80, 160].

5 Conclusions Statin-related psychiatric effects are rare and not preventable events, which are most likely to occur in susceptible patients with subclinical impairment of neurotransmitter pathways. Development of statin-associated psychiatric ADRs has been documented by case series and disproportion analysis performed on spontaneous reporting system databases. However, these signals have not been confirmed in the majority of studies that were designed to investigate specific psychiatric endpoints. Potential limitations of these studies are represented by the extreme variability of the criteria that were adopted for measurement of endpoints, based on a large number of different scales and questionnaires to assess neuropsychiatric disorders. At least some of these tools might not have been adequate to identify such events. Furthermore, the majority of the included studies were conducted in small populations, and they could not have had sufficient power to assess the risk of such rare events. The results obtained in investigations in elderly people, patients with cardiovascular disease or patients with a history of psychiatric disturbance do not allow us to conclude that these populations are at risk of developing statinrelated psychiatric effects. Nevertheless, because of limitations in the available studies, particular caution should be used when such patients require treatment with statins.

Several mechanisms, which are not mutually exclusive and are related mainly to inhibition of HMG-CoA reductase, have been proposed to account for the detrimental effects of statins on the CNS. These effects are likely dose-dependent class effects, which in some cases have also been observed with other antidyslipidaemic drugs, and they probably occur more frequently with statins endowed with a lipophilic chemical structure, allowing them to easily penetrate the blood–brain barrier. In particular, sexual dysfunction seems to be more a peripheral effect than a psychiatric effect, although a psychiatric contribution (reduced libido) cannot be ruled out. In the majority of cases, statin-related psychiatric disorders have resolved spontaneously after drug discontinuation and introduction of dietary restrictions. When these adverse reactions occur, it is important to note that hypocholesterolaemic treatment must be ensured anyway, especially in secondary prevention [176]. Therefore, the following options can be considered: (a) There is evidence that most statin-related psychiatric ADRs are transient conditions, which can resolve spontaneously without the need for drug discontinuation; when psychiatric symptoms are mild and can be tolerated by the patient, the possibility of maintaining the statin treatment for some weeks with close patient monitoring should be considered. (b) When psychiatric ADRs are moderate to severe, switching to a different statin (a hydrophilic one whenever possible) can be attempted to resolve symptoms. (c) There is evidence that the psychiatric effects of statins are dose dependent; on this basis, a dose reduction can be considered before definitive withdrawal. (d) Use of x-3 fatty acid supplements can be considered both for prophylaxis and for treatment; however, on the basis of the pathogenic hypotheses, this therapy will likely be effective only in cases where the symptoms result from increases in the AA to EPA ratio. It should be noted that in contrast to healthy volunteers, plasma x-3 fatty acid (especially DHA) has been negatively correlated with CSF levels of serotonin metabolites among violent subjects and early-onset alcoholics [149, 151]. Thus, supplementation with x-3 fatty acids cannot theoretically be recommended in these subjects, because of the potential risk of impulsive, violent and suicidal behaviour [177]. Similarly to supplements of x-3 fatty acids, supplements with coenzyme Q10 can be considered. (e) Use of psychotropic drugs has not proven to be effective in the management of statin-related psychiatric disorders and should be considered only in cases of persistent severe clinical symptoms. Overall, although knowledge of psychiatric events associated with statins has increased over the years, more

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information is warranted, and further clinical studies are recommended to gain objective evidence. Acknowledgments No source of funding was used in the preparation of this review. The authors (Marco Tuccori, Sabrina Montagnani, Stefania Mantarro, Alice Capogrosso-Sansone, Elisa Ruggiero, Alessandra Saporiti, Luca Antonioli, Matteo Fornai and Corrado Blandizzi) have no conflicts of interest that are directly relevant to the content of this review.

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