TY - JOUR
AU - Keen, Louise
AB - Abstract Aim 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. Further research is recommended in particular with older, female and lower socioeconomic samples. However, nurses should be alert to the risk and ready to intervene in cases of mood disturbance. Statins, mood states, depression, anxiety, anger, hostility Background The association between hypercholesterolaemia and coronary heart disease (CHD) is well documented1 and demonstrates the importance of a normal total cholesterol level. As the benefits of diet modification are limited2, lipid-lowering medications, in particular hydroxymethylglutaryl coenzyme A reductase inhibitors (statins), are currently the treatment of choice in reducing cholesterol3. Statins are particularly potent anticholesterolaemic agents4 and have not only been shown to reduce the incidence of coronary artery disease5 but have also been associated with reduced peri-operative risk of cardiovascular events6 due perhaps to their ability to regress coronary atherosclerosis7. Furthermore, it has been suggested that statins reduce the risk of Alzheimer’s disease8,9 and a recent meta-analysis tentatively suggested that statins may impede the development of cancer10. In light of such extensive therapeutic benefits, it is easy to understand why statins rank amongst the best-selling drugs in the world11. However, over the last 20 years questions have arisen about the possible side-effects and in particular the effects of statins on psychological health. With 7% of the UK population prescribed statins, a figure which increases annually by 30%3, it is vital that the potential negative effects are clarified. Early research suggested that, although low cholesterol levels decreased mortality from coronary heart disease12, they were also associated with an increase in violent or suicidal deaths13. Negative mood states such as anger and depression are risk factors for suicide and fatal accidents14 and could explain a relationship between low cholesterol and violent mortality. There is also evidence of biological mechanisms underpinning the adverse effect of cholesterol lowering on mood15,16. Lipids play an important role in the formation of the neuronal cell membrane and it has been suggested that decreased serum lipids lead to decreased membrane cholesterol which in turn lowers serotonergic activity. Aggression has been linked to low serotonergic activity17. Early studies found that both chronically low and medically lowered serum cholesterol were associated with an increased incidence of depression18–21. However, not all studies have supported the relationship between lipid-lowering treatment and adverse effect on mood22 and some have even proposed that statin therapy reduces the risk of depression23. Much of the research has focused on chronically low rather than medically lowered serum cholesterol, or measured the effect of lipid-lowering therapy in terms of clinical depression or suicide. As a result, those with undiagnosed mood disturbances were excluded. This review aims to clarify any adverse effects of statin therapy on mood focusing on the six elements of mood disturbance in the widely used Profile of Mood States (POMS) Short Form, namely: anxiety; depression; anger/hostility; fatigue; confusion and vigour24. Methods Search strategy Publications in 1980–2009 were identified through searching the Cinahl, Medline and Cochrane Library databases in November 2009. The search strategy paired the thesaurus and free terms “anxiety”, “depression”, “anger”, “hostility”, “fatigue”, “confusion”, “vigour” and “altered mood”, with each of the following: “statins”; “anticholesterolemic agents” and “antilipemic agents”. The risk of selection bias was reduced through careful selection of search terms25 which identified 320 papers. Using the ancestry approach, the reference lists of relevant papers were searched identifying a further seven relevant studies. Criteria for study inclusion Studies included in the review met four key criteria: Evidence of research rigour: The methodological quality of each study was assessed using tools developed by the critical appraisal skills programme (CASP) (www.phru.nhs.uk). As the study designs varied, questions from a number of CASP checklists were combined to form one critical appraisal tool suitable for use in this review. A summary of the appraisal process for all included studies is provided in Table 1. Due to the inconsistency reported in attempts to ‘quality score’ studies26, a common sense approach was applied to the appraisal process, ensuring the inclusion of papers which were felt to be robust in the majority if not all of the design elements27. Sample: Sample size was statistically large enough to detect treatment effect28. Study participants were older than 18 years but there was no upper age limit. No physical or psychological co-morbidities were excluded and serum cholesterol level was not limited. Studies which administered lipid-lowering treatment or placebo to those with excessively low or high serum cholesterol levels were considered unethical and therefore excluded29. Intervention: Treatment with one or more hydroxymethylglutaryl coenzyme A reductase inhibitor (statin) to be compared with treatment with non-statin anticholesterolaemic drugs, no lipid-lowering treatment or placebo. Variable doses within the normal prescribing range were included. Outcome: The primary outcome of interest was a change in one or more of the six key mood states: anxiety; depression; anger/hostility; fatigue; confusion and vigour. Papers which reported outcome by clinical diagnosis of mood disorder or by incidence of suicide or suicidal ideation were excluded. Papers reporting all other measurements of mood alteration were included. Table 1. Critical appraisal summary . Yes . Partially/unclear . No . Did the study address a clearly focussed question? 23, 37, 38, 39, 41, 42, 43 40 Was the study design and method appropriate to answer the question? 23, 37, 38, 39, 42, 43 40, 41 Was the sample recruited in an acceptable way? 23, 37, 39, 40, 43 38, 41, 42 Were controls (if used) selected in an appropriate way? 23, 37, 39, 40, 43 38, 41, 42 Were all participants accounted for at the end of the study? 23, 37, 38, 39, 40, 42, 43 41 Was the exposure procedure the same for all participants? 37, 38, 39, 40, 42 23, 41, 43 Was the outcome accurately measured in same way for all participants? 23, 37, 38, 39, 41, 42, 43 40 Have the authors taken account by controlling or adjusting for all potential confounding factors? 23, 37, 38, 39, 41, 42, 43 40 Are the results clearly presented? 23, 37, 38, 39, 40, 41, 42, 43 Are the results precise? 23, 37, 38, 39, 41, 42, 43 40 Do you believe the results? 23, 37, 38, 39, 41, 42, 43 40 Do the results have good generalisability? 23, 37, 38, 39, 40, 41, 42, 43 Are the results of the study consistent with other available evidence? 37, 38, 39, 40, 41, 42, 43 23 . Yes . Partially/unclear . No . Did the study address a clearly focussed question? 23, 37, 38, 39, 41, 42, 43 40 Was the study design and method appropriate to answer the question? 23, 37, 38, 39, 42, 43 40, 41 Was the sample recruited in an acceptable way? 23, 37, 39, 40, 43 38, 41, 42 Were controls (if used) selected in an appropriate way? 23, 37, 39, 40, 43 38, 41, 42 Were all participants accounted for at the end of the study? 23, 37, 38, 39, 40, 42, 43 41 Was the exposure procedure the same for all participants? 37, 38, 39, 40, 42 23, 41, 43 Was the outcome accurately measured in same way for all participants? 23, 37, 38, 39, 41, 42, 43 40 Have the authors taken account by controlling or adjusting for all potential confounding factors? 23, 37, 38, 39, 41, 42, 43 40 Are the results clearly presented? 23, 37, 38, 39, 40, 41, 42, 43 Are the results precise? 23, 37, 38, 39, 41, 42, 43 40 Do you believe the results? 23, 37, 38, 39, 41, 42, 43 40 Do the results have good generalisability? 23, 37, 38, 39, 40, 41, 42, 43 Are the results of the study consistent with other available evidence? 37, 38, 39, 40, 41, 42, 43 23 Reference number of included studies as detailed in Table 3. Open in new tab Table 1. Critical appraisal summary . Yes . Partially/unclear . No . Did the study address a clearly focussed question? 23, 37, 38, 39, 41, 42, 43 40 Was the study design and method appropriate to answer the question? 23, 37, 38, 39, 42, 43 40, 41 Was the sample recruited in an acceptable way? 23, 37, 39, 40, 43 38, 41, 42 Were controls (if used) selected in an appropriate way? 23, 37, 39, 40, 43 38, 41, 42 Were all participants accounted for at the end of the study? 23, 37, 38, 39, 40, 42, 43 41 Was the exposure procedure the same for all participants? 37, 38, 39, 40, 42 23, 41, 43 Was the outcome accurately measured in same way for all participants? 23, 37, 38, 39, 41, 42, 43 40 Have the authors taken account by controlling or adjusting for all potential confounding factors? 23, 37, 38, 39, 41, 42, 43 40 Are the results clearly presented? 23, 37, 38, 39, 40, 41, 42, 43 Are the results precise? 23, 37, 38, 39, 41, 42, 43 40 Do you believe the results? 23, 37, 38, 39, 41, 42, 43 40 Do the results have good generalisability? 23, 37, 38, 39, 40, 41, 42, 43 Are the results of the study consistent with other available evidence? 37, 38, 39, 40, 41, 42, 43 23 . Yes . Partially/unclear . No . Did the study address a clearly focussed question? 23, 37, 38, 39, 41, 42, 43 40 Was the study design and method appropriate to answer the question? 23, 37, 38, 39, 42, 43 40, 41 Was the sample recruited in an acceptable way? 23, 37, 39, 40, 43 38, 41, 42 Were controls (if used) selected in an appropriate way? 23, 37, 39, 40, 43 38, 41, 42 Were all participants accounted for at the end of the study? 23, 37, 38, 39, 40, 42, 43 41 Was the exposure procedure the same for all participants? 37, 38, 39, 40, 42 23, 41, 43 Was the outcome accurately measured in same way for all participants? 23, 37, 38, 39, 41, 42, 43 40 Have the authors taken account by controlling or adjusting for all potential confounding factors? 23, 37, 38, 39, 41, 42, 43 40 Are the results clearly presented? 23, 37, 38, 39, 40, 41, 42, 43 Are the results precise? 23, 37, 38, 39, 41, 42, 43 40 Do you believe the results? 23, 37, 38, 39, 41, 42, 43 40 Do the results have good generalisability? 23, 37, 38, 39, 40, 41, 42, 43 Are the results of the study consistent with other available evidence? 37, 38, 39, 40, 41, 42, 43 23 Reference number of included studies as detailed in Table 3. Open in new tab In addition to meeting the above criteria, only studies published in the English language and accessible via the extensive facilities of King’s College London library service were included. The titles, keywords and abstracts of articles sourced during the search process were reviewed to identify eligible papers. No papers were identified relating to fatigue, confusion or vigour. Of the 17 papers which were considered in full, nine were excluded for the following reasons: two studied the effects of naturally occurring rather than medically lowered hypocholesterolemia on mood19,21; one study30 failed to specify the class of lipid-lowering drugs included whilst four further papers studied outcomes other than mood31–34; and finally, two papers failed to clearly explain their methodology35,36. Eight papers25,37–43 met all the criteria for inclusion. Full details of the search are presented in Fig. 1. The thorough search of the literature indicated that no similar review had been previously undertaken which confirmed the need to further investigate the effect of statins on mood27. Figure 1. Open in new tabDownload slide Search strategy Data analysis A framework analysis approach44 involving a systematic process of sifting, charting and sorting the data into the following key themes: depression; anxiety and anger/hostility/aggression was utilised. Although the terms ‘confusion’, ’fatigue’ and vigour were included in the original search, none of the papers which met the inclusion criteria studied these three mood states. Furthermore, not all eight papers studied all mood states (Table 2). Table 2. Thematic analysis of included studies . Not studied . No effect . Negative effect . Positive effect . Was an effect on depression reported? 37, 38, 39, 40 41, 42, 43 23 Was an effect on anxiety reported? 40, 41 37, 38, 39, 42, 43 23 Was an effect on anger or hostility or aggression reported? 41 37, 38, 39, 42 40, 43 23 . Not studied . No effect . Negative effect . Positive effect . Was an effect on depression reported? 37, 38, 39, 40 41, 42, 43 23 Was an effect on anxiety reported? 40, 41 37, 38, 39, 42, 43 23 Was an effect on anger or hostility or aggression reported? 41 37, 38, 39, 42 40, 43 23 Reference number of included studies as detailed in Table 3. Open in new tab Table 2. Thematic analysis of included studies . Not studied . No effect . Negative effect . Positive effect . Was an effect on depression reported? 37, 38, 39, 40 41, 42, 43 23 Was an effect on anxiety reported? 40, 41 37, 38, 39, 42, 43 23 Was an effect on anger or hostility or aggression reported? 41 37, 38, 39, 42 40, 43 23 . Not studied . No effect . Negative effect . Positive effect . Was an effect on depression reported? 37, 38, 39, 40 41, 42, 43 23 Was an effect on anxiety reported? 40, 41 37, 38, 39, 42, 43 23 Was an effect on anger or hostility or aggression reported? 41 37, 38, 39, 42 40, 43 23 Reference number of included studies as detailed in Table 3. Open in new tab Findings Table 3 presents an overview of the eight papers included in this review. The findings of the selected papers are presented under the following headings: depression; anxiety and anger/hostility/aggression. Table 3. Summary of included papers Ref no. . Authors Year Country . Design . Measurement . Findings . Comments . [37] Wardle et al (1996) UK Double-blind RCT •Single-centre •Sample n = 621 men or women aged 40-75 years with cholesterol > 3.5 mmol/L and increased risk of MI, CVA, TIA, angina, CAD •Simvastatin 40 mg/d versus Simvastatin 20 mg/d versus placebo Cholesterol testing at baseline then every 12 weeks for year one and every 24 weeks thereafter •Measurement of mood occurred once at 152 week follow up •Measure: Effect on mood measured using the Profile of Mood States short form questionnaire Simvastatin at 20 mg/d and 40 mg/d does not adversely affect mood •Decrease in serum cholesterol with 20 mg/d and 40 mg/d was comparable at approximately 27% •Subgroup analysis for the oldest, those with greatest cholesterol decrease and men versus women still reveal no adverse effect of simvastatin on mood StrengthsDouble-blind RCT •Adequate sample size •Compares intervention versus placebo at differing dose •No exclusion for previous mood disorder •Controls for confounding by non-compliance - baseline groups comparable •Attrition reported •Limitations Studies only 1 statin Limited generalisability to males at risk of CVD •Excludes significant physical co-morbidity •Measurement of mood occurs at 30 months and not at baseline [38] Muldoon et al. (2000) USA Double-blind, RCT •Single centre •Sample n = 209 adults aged 24–60 with mild/moderate hypercholesterolaemia •Lovastatin 20 mg/d versus placebo Cholesterol testing at baseline and 4 other times over 6 month trial period •Measures taken at baseline and at 6 months •Measures: Medical Outcomes Study Short Form (depression, hostility, mood), Daily Diary (mood) No effects on psychological well-being were noted, even in those with greatest % reduction or lowest post-treatment serum cholesterol levels StrengthsDouble-blind RCT •Correlates cholesterol level to outcome •Adequate sample size •Compares intervention with control •Baseline groups comparable •Excludes previous lipid-lowering pharmacotherapy •Sufficient follow-up time •Multiple outcome measures employed •Attrition reported Limitations •Studies only 1 statin Limited generalisability to white, well-educated sample •Sample recruitment via media •Exclusion of physical and psychiatric co-morbidity •6 month retrospective mood testing [39] Stewart et al. (2000) Australia and New Zealand Double-blind, RCT •36 centres across Australia and New Zealand •Sample n = 1130 adults aged 31–74 with stable coronary artery disease and serum cholesterol between 155–271 mg/dL (4–7 mmol/L) •Pravastatin 40 mg/d versus placebo Cholesterol testing at baseline, 6 months, 1, 2 and 4 years •Measures taken at baseline, after 6 months, 1, 2 and 4 years •Measures: General Health Questionnaire (anxiety and depression), Spielberger Anger Expression Scale (anger) •In addition adverse life events, alcohol consumption, other medication use, social isolation also self-reported retrospectively at each visit •Cholesterol testing at baseline, at 12 weeks and at 24 weeks •Measures taken at baseline, 12 weeks and 24 weeks No difference in primary or secondary outcomes noted between treatment and control group •No difference in outcomes in pre-specified subgroups: > 70 year olds; those with serum cholesterol in lowest 10% at baseline; those with pre-existing psychiatric illness; those with high psychological test scores at baseline •No association between psychological well-being and decrease in serum cholesterol found •Serum cholesterol lowered by Mediterranean diet by 7.7% and by Simvastatin by 20.8% StrengthsDouble-blind RCT •Large number of centres •Sufficient sample size •Compares intervention with control •No exclusion for previous mood disorder •Excludes previous lipid-lowering therapy •Controls confounding by smoking and BMI •Baseline groups comparable •Extensive follow-up period •Numerous measurements of mood Limitations •Studies only 1 statin •Limited generalisability to males with history of MI or unstable angina •Excludes significant co-morbidity •Retrospective completion of questionnaires to assess mood [43] Hyyppa et al (2003) Finland Double-blind RCT with crossover •5 industrial plants •Sample n = 120 hypercholesterolaemic men aged 35–64 years with serum cholesterol 6–8 mmol/L at baseline •Mediterranean diet and/or Simvastatin 20 mg/d versus placebo Measures: Brief Symptom Inventory (somatization, depression, anxiety, hostility), Strauss Scale of Aggression (formed 2 questionnaires—1 completed by participant, 1 by participant's partner Simvastatin increases somatization, depression and self-reported aggressiveness •Mood changes still evident after controlling for age, BMI and change in serum cholesterol and hormones •Mediterranean diet does not affect mood or serum hormone levels StrengthsDouble-blind RCT with crossover •Adequate sample size •Compares 2 treatments with control •No exclusion for previous mood or psychiatric disorder •Controls confounding of non-compliance •Baseline groups comparable •Both participant and their partner completed questionnaire on aggression •Limitations Limited generalisability to working class males •Attrition reported •Excludes those with significant physical co-morbidity or with BMI < 32 kg/m2 •Short follow-up time •Compliance with Mediterranean diet difficult to measure [23] Young-Xu et al. (2003) USA Observational cohort study •Single centre •Sample n = 606 adults of any age with Coronary Artery Disease •Statin use versus non-statin use versus non lipid-lowering medication Cholesterol testing at baseline and at follow up •Measures taken at baseline and annually thereafter up to 7 years •Measures: Kellner Symptom, Buss-Durkee and Cook–Medley questionnaires (depression, anxiety and hostility), Locus of Control Schedule (health related behaviour), Berkman–Syme Social Network Index (social support) Continuous statin usage associated with decreased depression, anxiety and hostility •Positive effect on depression, anxiety and hostility is cumulative. •Similar but weaker association with non-statin LLDs-lowering drugs •The positive effect on depression, anxiety and hostility is not correlated with decreased total cholesterol StrengthsCompares different LLDs-lowering drugs •Large sample size •Comparison with control group •No exclusion for previous mood disorder •Data adjusted for potential confounders •Extensive follow-up time •Several outcome measures employed •Attrition reported •Compares cumulative, intermittent and non-treatment effect on mood •Limitations Not an RCT •Limited generalisability to well-educated males with Coronary Artery Disease •Does not test an intervention •All non-cardiac morbidity excluded •Questionnaires completed at clinic or at home Strengths [42] Morales et al. (2006) USA Double-blind, RCT •Single centre •Sample n = 80 adults aged 65 and over with mild/moderate hypercholesterolaemia •Simvastatin (increasing dose to 20 mg/d) versus placebo Cholesterol tested/ daily diaries collected at baseline and weeks 1, 3, 5, 7, 9, 11, 13 and 15 •Measures taken at baseline and weeks 7, 11 and 15 •Measures: CES-D (depression), Profile of Mood States and Apathy Evaluation Scale (mood). •Daily completion of Lawton Positive Affect and Negative Affect rating scales •Daily diary of events outside the usual routine—evaluated as positive or negative by independent raters using a “reasonable person” standard Simvastatin does not cause depression •Simvastatin associated with a time-related decrease in positive affect which was greatest in the subgroup with total cholesterol in the lowest quartile (< 148) •Simvastatin causes time-limited increase in probability that negative events lead to negative affect Double-blind RCT •Tests dose-related effects •Adequate sample size •Compares intervention with control •Excludes previous lipid-lowering pharmacotherapy •Controls for confounding - baseline groups comparable Regular outcome measurement Attrition reported •Limitations Studies only 1 statin Limited generalisability to white, well-educated senior citizens •Sample recruitment via media •Excludes previous/current mood disorder Insufficient follow-up time Use of diaries maybe unreliable [41] Agostini et al. (2007) USA Observational Cohort Study •Multi centre—unspecified number of primary health clinics •Sample n = 756 ambulatory, English speaking adults aged 65 years and over •No new intervention—patients with current statin prescription: Lovastatin; Atorvastatin, pravastatin; simvastatin compared with non-statin users Baseline cholesterol level taken from medical record on nearest date before enrolment •Measures taken by interview at baseline and 1 year follow up •Measure: Center for Epidemiologic Studies Depression Scale (CES-D) Chronic statin use does not adversely affect depressive symptoms •Slight increase in depressive symptoms in older statin users (over 80) with > 3 co-morbidities •Statin users are prescribed more medications with mean average 6.6 versus 4.6 medications in non-statin users StrengthsCompares statin users to non-statin users •Adequate sample size •Comparison with control group •No exclusion for previous mood disorder, co-morbidity or polypharmacy •Data adjustment for co-morbidity, polypharmacy, smoking and alcohol use •Studies older patients with co-morbidity •Limitations Not an RCT •No comparison between statins •Limited generalisability to older, white, well-educated, male veterans •Does not test a new intervention •No adjustment made for co-morbidity diagnosed after start of trial •Follow up only once after 1 year •Mood questionnaires potentially ineffective in older men •Attrition not reported Strengths [40] Olson et al (2008) USA Retrospective reanalysis design 4 centres •Sample n = 954 women aged 18 or over having a clinical indicated angiogram for chest pain and/or myocardial ischaemia One retrospective measurement taken for cholesterol •Single measurements taken from previous study •Measures: Cook–Medley Questionnaire (hostility and aggression), Beck Depression Inventory (depression)> Aggression is greater in those taking LLDs •Depression and hostility is not greater in those taking LLDs •In a subgroup of those with low cholesterol levels, only those taking LLDs had greater aggression •Greater aggression also reported when only statin usage was considered StrengthsCompares statins with non-statin LLDs •Adequate sample size •Focuses on women due to gap in research •No exclusion for previous mood disorder •Limitations Not an RCT •Does not compare different statins •Limited generalisability to women undergoing angiogram •Excludes significant physical co-morbidity •Does not test an intervention •No adjustment for differing baseline characteristics •Draws data from a previous study almost 10 years ago •No outcome comparison over time Ref no. . Authors Year Country . Design . Measurement . Findings . Comments . [37] Wardle et al (1996) UK Double-blind RCT •Single-centre •Sample n = 621 men or women aged 40-75 years with cholesterol > 3.5 mmol/L and increased risk of MI, CVA, TIA, angina, CAD •Simvastatin 40 mg/d versus Simvastatin 20 mg/d versus placebo Cholesterol testing at baseline then every 12 weeks for year one and every 24 weeks thereafter •Measurement of mood occurred once at 152 week follow up •Measure: Effect on mood measured using the Profile of Mood States short form questionnaire Simvastatin at 20 mg/d and 40 mg/d does not adversely affect mood •Decrease in serum cholesterol with 20 mg/d and 40 mg/d was comparable at approximately 27% •Subgroup analysis for the oldest, those with greatest cholesterol decrease and men versus women still reveal no adverse effect of simvastatin on mood StrengthsDouble-blind RCT •Adequate sample size •Compares intervention versus placebo at differing dose •No exclusion for previous mood disorder •Controls for confounding by non-compliance - baseline groups comparable •Attrition reported •Limitations Studies only 1 statin Limited generalisability to males at risk of CVD •Excludes significant physical co-morbidity •Measurement of mood occurs at 30 months and not at baseline [38] Muldoon et al. (2000) USA Double-blind, RCT •Single centre •Sample n = 209 adults aged 24–60 with mild/moderate hypercholesterolaemia •Lovastatin 20 mg/d versus placebo Cholesterol testing at baseline and 4 other times over 6 month trial period •Measures taken at baseline and at 6 months •Measures: Medical Outcomes Study Short Form (depression, hostility, mood), Daily Diary (mood) No effects on psychological well-being were noted, even in those with greatest % reduction or lowest post-treatment serum cholesterol levels StrengthsDouble-blind RCT •Correlates cholesterol level to outcome •Adequate sample size •Compares intervention with control •Baseline groups comparable •Excludes previous lipid-lowering pharmacotherapy •Sufficient follow-up time •Multiple outcome measures employed •Attrition reported Limitations •Studies only 1 statin Limited generalisability to white, well-educated sample •Sample recruitment via media •Exclusion of physical and psychiatric co-morbidity •6 month retrospective mood testing [39] Stewart et al. (2000) Australia and New Zealand Double-blind, RCT •36 centres across Australia and New Zealand •Sample n = 1130 adults aged 31–74 with stable coronary artery disease and serum cholesterol between 155–271 mg/dL (4–7 mmol/L) •Pravastatin 40 mg/d versus placebo Cholesterol testing at baseline, 6 months, 1, 2 and 4 years •Measures taken at baseline, after 6 months, 1, 2 and 4 years •Measures: General Health Questionnaire (anxiety and depression), Spielberger Anger Expression Scale (anger) •In addition adverse life events, alcohol consumption, other medication use, social isolation also self-reported retrospectively at each visit •Cholesterol testing at baseline, at 12 weeks and at 24 weeks •Measures taken at baseline, 12 weeks and 24 weeks No difference in primary or secondary outcomes noted between treatment and control group •No difference in outcomes in pre-specified subgroups: > 70 year olds; those with serum cholesterol in lowest 10% at baseline; those with pre-existing psychiatric illness; those with high psychological test scores at baseline •No association between psychological well-being and decrease in serum cholesterol found •Serum cholesterol lowered by Mediterranean diet by 7.7% and by Simvastatin by 20.8% StrengthsDouble-blind RCT •Large number of centres •Sufficient sample size •Compares intervention with control •No exclusion for previous mood disorder •Excludes previous lipid-lowering therapy •Controls confounding by smoking and BMI •Baseline groups comparable •Extensive follow-up period •Numerous measurements of mood Limitations •Studies only 1 statin •Limited generalisability to males with history of MI or unstable angina •Excludes significant co-morbidity •Retrospective completion of questionnaires to assess mood [43] Hyyppa et al (2003) Finland Double-blind RCT with crossover •5 industrial plants •Sample n = 120 hypercholesterolaemic men aged 35–64 years with serum cholesterol 6–8 mmol/L at baseline •Mediterranean diet and/or Simvastatin 20 mg/d versus placebo Measures: Brief Symptom Inventory (somatization, depression, anxiety, hostility), Strauss Scale of Aggression (formed 2 questionnaires—1 completed by participant, 1 by participant's partner Simvastatin increases somatization, depression and self-reported aggressiveness •Mood changes still evident after controlling for age, BMI and change in serum cholesterol and hormones •Mediterranean diet does not affect mood or serum hormone levels StrengthsDouble-blind RCT with crossover •Adequate sample size •Compares 2 treatments with control •No exclusion for previous mood or psychiatric disorder •Controls confounding of non-compliance •Baseline groups comparable •Both participant and their partner completed questionnaire on aggression •Limitations Limited generalisability to working class males •Attrition reported •Excludes those with significant physical co-morbidity or with BMI < 32 kg/m2 •Short follow-up time •Compliance with Mediterranean diet difficult to measure [23] Young-Xu et al. (2003) USA Observational cohort study •Single centre •Sample n = 606 adults of any age with Coronary Artery Disease •Statin use versus non-statin use versus non lipid-lowering medication Cholesterol testing at baseline and at follow up •Measures taken at baseline and annually thereafter up to 7 years •Measures: Kellner Symptom, Buss-Durkee and Cook–Medley questionnaires (depression, anxiety and hostility), Locus of Control Schedule (health related behaviour), Berkman–Syme Social Network Index (social support) Continuous statin usage associated with decreased depression, anxiety and hostility •Positive effect on depression, anxiety and hostility is cumulative. •Similar but weaker association with non-statin LLDs-lowering drugs •The positive effect on depression, anxiety and hostility is not correlated with decreased total cholesterol StrengthsCompares different LLDs-lowering drugs •Large sample size •Comparison with control group •No exclusion for previous mood disorder •Data adjusted for potential confounders •Extensive follow-up time •Several outcome measures employed •Attrition reported •Compares cumulative, intermittent and non-treatment effect on mood •Limitations Not an RCT •Limited generalisability to well-educated males with Coronary Artery Disease •Does not test an intervention •All non-cardiac morbidity excluded •Questionnaires completed at clinic or at home Strengths [42] Morales et al. (2006) USA Double-blind, RCT •Single centre •Sample n = 80 adults aged 65 and over with mild/moderate hypercholesterolaemia •Simvastatin (increasing dose to 20 mg/d) versus placebo Cholesterol tested/ daily diaries collected at baseline and weeks 1, 3, 5, 7, 9, 11, 13 and 15 •Measures taken at baseline and weeks 7, 11 and 15 •Measures: CES-D (depression), Profile of Mood States and Apathy Evaluation Scale (mood). •Daily completion of Lawton Positive Affect and Negative Affect rating scales •Daily diary of events outside the usual routine—evaluated as positive or negative by independent raters using a “reasonable person” standard Simvastatin does not cause depression •Simvastatin associated with a time-related decrease in positive affect which was greatest in the subgroup with total cholesterol in the lowest quartile (< 148) •Simvastatin causes time-limited increase in probability that negative events lead to negative affect Double-blind RCT •Tests dose-related effects •Adequate sample size •Compares intervention with control •Excludes previous lipid-lowering pharmacotherapy •Controls for confounding - baseline groups comparable Regular outcome measurement Attrition reported •Limitations Studies only 1 statin Limited generalisability to white, well-educated senior citizens •Sample recruitment via media •Excludes previous/current mood disorder Insufficient follow-up time Use of diaries maybe unreliable [41] Agostini et al. (2007) USA Observational Cohort Study •Multi centre—unspecified number of primary health clinics •Sample n = 756 ambulatory, English speaking adults aged 65 years and over •No new intervention—patients with current statin prescription: Lovastatin; Atorvastatin, pravastatin; simvastatin compared with non-statin users Baseline cholesterol level taken from medical record on nearest date before enrolment •Measures taken by interview at baseline and 1 year follow up •Measure: Center for Epidemiologic Studies Depression Scale (CES-D) Chronic statin use does not adversely affect depressive symptoms •Slight increase in depressive symptoms in older statin users (over 80) with > 3 co-morbidities •Statin users are prescribed more medications with mean average 6.6 versus 4.6 medications in non-statin users StrengthsCompares statin users to non-statin users •Adequate sample size •Comparison with control group •No exclusion for previous mood disorder, co-morbidity or polypharmacy •Data adjustment for co-morbidity, polypharmacy, smoking and alcohol use •Studies older patients with co-morbidity •Limitations Not an RCT •No comparison between statins •Limited generalisability to older, white, well-educated, male veterans •Does not test a new intervention •No adjustment made for co-morbidity diagnosed after start of trial •Follow up only once after 1 year •Mood questionnaires potentially ineffective in older men •Attrition not reported Strengths [40] Olson et al (2008) USA Retrospective reanalysis design 4 centres •Sample n = 954 women aged 18 or over having a clinical indicated angiogram for chest pain and/or myocardial ischaemia One retrospective measurement taken for cholesterol •Single measurements taken from previous study •Measures: Cook–Medley Questionnaire (hostility and aggression), Beck Depression Inventory (depression)> Aggression is greater in those taking LLDs •Depression and hostility is not greater in those taking LLDs •In a subgroup of those with low cholesterol levels, only those taking LLDs had greater aggression •Greater aggression also reported when only statin usage was considered StrengthsCompares statins with non-statin LLDs •Adequate sample size •Focuses on women due to gap in research •No exclusion for previous mood disorder •Limitations Not an RCT •Does not compare different statins •Limited generalisability to women undergoing angiogram •Excludes significant physical co-morbidity •Does not test an intervention •No adjustment for differing baseline characteristics •Draws data from a previous study almost 10 years ago •No outcome comparison over time Open in new tab Table 3. Summary of included papers Ref no. . Authors Year Country . Design . Measurement . Findings . Comments . [37] Wardle et al (1996) UK Double-blind RCT •Single-centre •Sample n = 621 men or women aged 40-75 years with cholesterol > 3.5 mmol/L and increased risk of MI, CVA, TIA, angina, CAD •Simvastatin 40 mg/d versus Simvastatin 20 mg/d versus placebo Cholesterol testing at baseline then every 12 weeks for year one and every 24 weeks thereafter •Measurement of mood occurred once at 152 week follow up •Measure: Effect on mood measured using the Profile of Mood States short form questionnaire Simvastatin at 20 mg/d and 40 mg/d does not adversely affect mood •Decrease in serum cholesterol with 20 mg/d and 40 mg/d was comparable at approximately 27% •Subgroup analysis for the oldest, those with greatest cholesterol decrease and men versus women still reveal no adverse effect of simvastatin on mood StrengthsDouble-blind RCT •Adequate sample size •Compares intervention versus placebo at differing dose •No exclusion for previous mood disorder •Controls for confounding by non-compliance - baseline groups comparable •Attrition reported •Limitations Studies only 1 statin Limited generalisability to males at risk of CVD •Excludes significant physical co-morbidity •Measurement of mood occurs at 30 months and not at baseline [38] Muldoon et al. (2000) USA Double-blind, RCT •Single centre •Sample n = 209 adults aged 24–60 with mild/moderate hypercholesterolaemia •Lovastatin 20 mg/d versus placebo Cholesterol testing at baseline and 4 other times over 6 month trial period •Measures taken at baseline and at 6 months •Measures: Medical Outcomes Study Short Form (depression, hostility, mood), Daily Diary (mood) No effects on psychological well-being were noted, even in those with greatest % reduction or lowest post-treatment serum cholesterol levels StrengthsDouble-blind RCT •Correlates cholesterol level to outcome •Adequate sample size •Compares intervention with control •Baseline groups comparable •Excludes previous lipid-lowering pharmacotherapy •Sufficient follow-up time •Multiple outcome measures employed •Attrition reported Limitations •Studies only 1 statin Limited generalisability to white, well-educated sample •Sample recruitment via media •Exclusion of physical and psychiatric co-morbidity •6 month retrospective mood testing [39] Stewart et al. (2000) Australia and New Zealand Double-blind, RCT •36 centres across Australia and New Zealand •Sample n = 1130 adults aged 31–74 with stable coronary artery disease and serum cholesterol between 155–271 mg/dL (4–7 mmol/L) •Pravastatin 40 mg/d versus placebo Cholesterol testing at baseline, 6 months, 1, 2 and 4 years •Measures taken at baseline, after 6 months, 1, 2 and 4 years •Measures: General Health Questionnaire (anxiety and depression), Spielberger Anger Expression Scale (anger) •In addition adverse life events, alcohol consumption, other medication use, social isolation also self-reported retrospectively at each visit •Cholesterol testing at baseline, at 12 weeks and at 24 weeks •Measures taken at baseline, 12 weeks and 24 weeks No difference in primary or secondary outcomes noted between treatment and control group •No difference in outcomes in pre-specified subgroups: > 70 year olds; those with serum cholesterol in lowest 10% at baseline; those with pre-existing psychiatric illness; those with high psychological test scores at baseline •No association between psychological well-being and decrease in serum cholesterol found •Serum cholesterol lowered by Mediterranean diet by 7.7% and by Simvastatin by 20.8% StrengthsDouble-blind RCT •Large number of centres •Sufficient sample size •Compares intervention with control •No exclusion for previous mood disorder •Excludes previous lipid-lowering therapy •Controls confounding by smoking and BMI •Baseline groups comparable •Extensive follow-up period •Numerous measurements of mood Limitations •Studies only 1 statin •Limited generalisability to males with history of MI or unstable angina •Excludes significant co-morbidity •Retrospective completion of questionnaires to assess mood [43] Hyyppa et al (2003) Finland Double-blind RCT with crossover •5 industrial plants •Sample n = 120 hypercholesterolaemic men aged 35–64 years with serum cholesterol 6–8 mmol/L at baseline •Mediterranean diet and/or Simvastatin 20 mg/d versus placebo Measures: Brief Symptom Inventory (somatization, depression, anxiety, hostility), Strauss Scale of Aggression (formed 2 questionnaires—1 completed by participant, 1 by participant's partner Simvastatin increases somatization, depression and self-reported aggressiveness •Mood changes still evident after controlling for age, BMI and change in serum cholesterol and hormones •Mediterranean diet does not affect mood or serum hormone levels StrengthsDouble-blind RCT with crossover •Adequate sample size •Compares 2 treatments with control •No exclusion for previous mood or psychiatric disorder •Controls confounding of non-compliance •Baseline groups comparable •Both participant and their partner completed questionnaire on aggression •Limitations Limited generalisability to working class males •Attrition reported •Excludes those with significant physical co-morbidity or with BMI < 32 kg/m2 •Short follow-up time •Compliance with Mediterranean diet difficult to measure [23] Young-Xu et al. (2003) USA Observational cohort study •Single centre •Sample n = 606 adults of any age with Coronary Artery Disease •Statin use versus non-statin use versus non lipid-lowering medication Cholesterol testing at baseline and at follow up •Measures taken at baseline and annually thereafter up to 7 years •Measures: Kellner Symptom, Buss-Durkee and Cook–Medley questionnaires (depression, anxiety and hostility), Locus of Control Schedule (health related behaviour), Berkman–Syme Social Network Index (social support) Continuous statin usage associated with decreased depression, anxiety and hostility •Positive effect on depression, anxiety and hostility is cumulative. •Similar but weaker association with non-statin LLDs-lowering drugs •The positive effect on depression, anxiety and hostility is not correlated with decreased total cholesterol StrengthsCompares different LLDs-lowering drugs •Large sample size •Comparison with control group •No exclusion for previous mood disorder •Data adjusted for potential confounders •Extensive follow-up time •Several outcome measures employed •Attrition reported •Compares cumulative, intermittent and non-treatment effect on mood •Limitations Not an RCT •Limited generalisability to well-educated males with Coronary Artery Disease •Does not test an intervention •All non-cardiac morbidity excluded •Questionnaires completed at clinic or at home Strengths [42] Morales et al. (2006) USA Double-blind, RCT •Single centre •Sample n = 80 adults aged 65 and over with mild/moderate hypercholesterolaemia •Simvastatin (increasing dose to 20 mg/d) versus placebo Cholesterol tested/ daily diaries collected at baseline and weeks 1, 3, 5, 7, 9, 11, 13 and 15 •Measures taken at baseline and weeks 7, 11 and 15 •Measures: CES-D (depression), Profile of Mood States and Apathy Evaluation Scale (mood). •Daily completion of Lawton Positive Affect and Negative Affect rating scales •Daily diary of events outside the usual routine—evaluated as positive or negative by independent raters using a “reasonable person” standard Simvastatin does not cause depression •Simvastatin associated with a time-related decrease in positive affect which was greatest in the subgroup with total cholesterol in the lowest quartile (< 148) •Simvastatin causes time-limited increase in probability that negative events lead to negative affect Double-blind RCT •Tests dose-related effects •Adequate sample size •Compares intervention with control •Excludes previous lipid-lowering pharmacotherapy •Controls for confounding - baseline groups comparable Regular outcome measurement Attrition reported •Limitations Studies only 1 statin Limited generalisability to white, well-educated senior citizens •Sample recruitment via media •Excludes previous/current mood disorder Insufficient follow-up time Use of diaries maybe unreliable [41] Agostini et al. (2007) USA Observational Cohort Study •Multi centre—unspecified number of primary health clinics •Sample n = 756 ambulatory, English speaking adults aged 65 years and over •No new intervention—patients with current statin prescription: Lovastatin; Atorvastatin, pravastatin; simvastatin compared with non-statin users Baseline cholesterol level taken from medical record on nearest date before enrolment •Measures taken by interview at baseline and 1 year follow up •Measure: Center for Epidemiologic Studies Depression Scale (CES-D) Chronic statin use does not adversely affect depressive symptoms •Slight increase in depressive symptoms in older statin users (over 80) with > 3 co-morbidities •Statin users are prescribed more medications with mean average 6.6 versus 4.6 medications in non-statin users StrengthsCompares statin users to non-statin users •Adequate sample size •Comparison with control group •No exclusion for previous mood disorder, co-morbidity or polypharmacy •Data adjustment for co-morbidity, polypharmacy, smoking and alcohol use •Studies older patients with co-morbidity •Limitations Not an RCT •No comparison between statins •Limited generalisability to older, white, well-educated, male veterans •Does not test a new intervention •No adjustment made for co-morbidity diagnosed after start of trial •Follow up only once after 1 year •Mood questionnaires potentially ineffective in older men •Attrition not reported Strengths [40] Olson et al (2008) USA Retrospective reanalysis design 4 centres •Sample n = 954 women aged 18 or over having a clinical indicated angiogram for chest pain and/or myocardial ischaemia One retrospective measurement taken for cholesterol •Single measurements taken from previous study •Measures: Cook–Medley Questionnaire (hostility and aggression), Beck Depression Inventory (depression)> Aggression is greater in those taking LLDs •Depression and hostility is not greater in those taking LLDs •In a subgroup of those with low cholesterol levels, only those taking LLDs had greater aggression •Greater aggression also reported when only statin usage was considered StrengthsCompares statins with non-statin LLDs •Adequate sample size •Focuses on women due to gap in research •No exclusion for previous mood disorder •Limitations Not an RCT •Does not compare different statins •Limited generalisability to women undergoing angiogram •Excludes significant physical co-morbidity •Does not test an intervention •No adjustment for differing baseline characteristics •Draws data from a previous study almost 10 years ago •No outcome comparison over time Ref no. . Authors Year Country . Design . Measurement . Findings . Comments . [37] Wardle et al (1996) UK Double-blind RCT •Single-centre •Sample n = 621 men or women aged 40-75 years with cholesterol > 3.5 mmol/L and increased risk of MI, CVA, TIA, angina, CAD •Simvastatin 40 mg/d versus Simvastatin 20 mg/d versus placebo Cholesterol testing at baseline then every 12 weeks for year one and every 24 weeks thereafter •Measurement of mood occurred once at 152 week follow up •Measure: Effect on mood measured using the Profile of Mood States short form questionnaire Simvastatin at 20 mg/d and 40 mg/d does not adversely affect mood •Decrease in serum cholesterol with 20 mg/d and 40 mg/d was comparable at approximately 27% •Subgroup analysis for the oldest, those with greatest cholesterol decrease and men versus women still reveal no adverse effect of simvastatin on mood StrengthsDouble-blind RCT •Adequate sample size •Compares intervention versus placebo at differing dose •No exclusion for previous mood disorder •Controls for confounding by non-compliance - baseline groups comparable •Attrition reported •Limitations Studies only 1 statin Limited generalisability to males at risk of CVD •Excludes significant physical co-morbidity •Measurement of mood occurs at 30 months and not at baseline [38] Muldoon et al. (2000) USA Double-blind, RCT •Single centre •Sample n = 209 adults aged 24–60 with mild/moderate hypercholesterolaemia •Lovastatin 20 mg/d versus placebo Cholesterol testing at baseline and 4 other times over 6 month trial period •Measures taken at baseline and at 6 months •Measures: Medical Outcomes Study Short Form (depression, hostility, mood), Daily Diary (mood) No effects on psychological well-being were noted, even in those with greatest % reduction or lowest post-treatment serum cholesterol levels StrengthsDouble-blind RCT •Correlates cholesterol level to outcome •Adequate sample size •Compares intervention with control •Baseline groups comparable •Excludes previous lipid-lowering pharmacotherapy •Sufficient follow-up time •Multiple outcome measures employed •Attrition reported Limitations •Studies only 1 statin Limited generalisability to white, well-educated sample •Sample recruitment via media •Exclusion of physical and psychiatric co-morbidity •6 month retrospective mood testing [39] Stewart et al. (2000) Australia and New Zealand Double-blind, RCT •36 centres across Australia and New Zealand •Sample n = 1130 adults aged 31–74 with stable coronary artery disease and serum cholesterol between 155–271 mg/dL (4–7 mmol/L) •Pravastatin 40 mg/d versus placebo Cholesterol testing at baseline, 6 months, 1, 2 and 4 years •Measures taken at baseline, after 6 months, 1, 2 and 4 years •Measures: General Health Questionnaire (anxiety and depression), Spielberger Anger Expression Scale (anger) •In addition adverse life events, alcohol consumption, other medication use, social isolation also self-reported retrospectively at each visit •Cholesterol testing at baseline, at 12 weeks and at 24 weeks •Measures taken at baseline, 12 weeks and 24 weeks No difference in primary or secondary outcomes noted between treatment and control group •No difference in outcomes in pre-specified subgroups: > 70 year olds; those with serum cholesterol in lowest 10% at baseline; those with pre-existing psychiatric illness; those with high psychological test scores at baseline •No association between psychological well-being and decrease in serum cholesterol found •Serum cholesterol lowered by Mediterranean diet by 7.7% and by Simvastatin by 20.8% StrengthsDouble-blind RCT •Large number of centres •Sufficient sample size •Compares intervention with control •No exclusion for previous mood disorder •Excludes previous lipid-lowering therapy •Controls confounding by smoking and BMI •Baseline groups comparable •Extensive follow-up period •Numerous measurements of mood Limitations •Studies only 1 statin •Limited generalisability to males with history of MI or unstable angina •Excludes significant co-morbidity •Retrospective completion of questionnaires to assess mood [43] Hyyppa et al (2003) Finland Double-blind RCT with crossover •5 industrial plants •Sample n = 120 hypercholesterolaemic men aged 35–64 years with serum cholesterol 6–8 mmol/L at baseline •Mediterranean diet and/or Simvastatin 20 mg/d versus placebo Measures: Brief Symptom Inventory (somatization, depression, anxiety, hostility), Strauss Scale of Aggression (formed 2 questionnaires—1 completed by participant, 1 by participant's partner Simvastatin increases somatization, depression and self-reported aggressiveness •Mood changes still evident after controlling for age, BMI and change in serum cholesterol and hormones •Mediterranean diet does not affect mood or serum hormone levels StrengthsDouble-blind RCT with crossover •Adequate sample size •Compares 2 treatments with control •No exclusion for previous mood or psychiatric disorder •Controls confounding of non-compliance •Baseline groups comparable •Both participant and their partner completed questionnaire on aggression •Limitations Limited generalisability to working class males •Attrition reported •Excludes those with significant physical co-morbidity or with BMI < 32 kg/m2 •Short follow-up time •Compliance with Mediterranean diet difficult to measure [23] Young-Xu et al. (2003) USA Observational cohort study •Single centre •Sample n = 606 adults of any age with Coronary Artery Disease •Statin use versus non-statin use versus non lipid-lowering medication Cholesterol testing at baseline and at follow up •Measures taken at baseline and annually thereafter up to 7 years •Measures: Kellner Symptom, Buss-Durkee and Cook–Medley questionnaires (depression, anxiety and hostility), Locus of Control Schedule (health related behaviour), Berkman–Syme Social Network Index (social support) Continuous statin usage associated with decreased depression, anxiety and hostility •Positive effect on depression, anxiety and hostility is cumulative. •Similar but weaker association with non-statin LLDs-lowering drugs •The positive effect on depression, anxiety and hostility is not correlated with decreased total cholesterol StrengthsCompares different LLDs-lowering drugs •Large sample size •Comparison with control group •No exclusion for previous mood disorder •Data adjusted for potential confounders •Extensive follow-up time •Several outcome measures employed •Attrition reported •Compares cumulative, intermittent and non-treatment effect on mood •Limitations Not an RCT •Limited generalisability to well-educated males with Coronary Artery Disease •Does not test an intervention •All non-cardiac morbidity excluded •Questionnaires completed at clinic or at home Strengths [42] Morales et al. (2006) USA Double-blind, RCT •Single centre •Sample n = 80 adults aged 65 and over with mild/moderate hypercholesterolaemia •Simvastatin (increasing dose to 20 mg/d) versus placebo Cholesterol tested/ daily diaries collected at baseline and weeks 1, 3, 5, 7, 9, 11, 13 and 15 •Measures taken at baseline and weeks 7, 11 and 15 •Measures: CES-D (depression), Profile of Mood States and Apathy Evaluation Scale (mood). •Daily completion of Lawton Positive Affect and Negative Affect rating scales •Daily diary of events outside the usual routine—evaluated as positive or negative by independent raters using a “reasonable person” standard Simvastatin does not cause depression •Simvastatin associated with a time-related decrease in positive affect which was greatest in the subgroup with total cholesterol in the lowest quartile (< 148) •Simvastatin causes time-limited increase in probability that negative events lead to negative affect Double-blind RCT •Tests dose-related effects •Adequate sample size •Compares intervention with control •Excludes previous lipid-lowering pharmacotherapy •Controls for confounding - baseline groups comparable Regular outcome measurement Attrition reported •Limitations Studies only 1 statin Limited generalisability to white, well-educated senior citizens •Sample recruitment via media •Excludes previous/current mood disorder Insufficient follow-up time Use of diaries maybe unreliable [41] Agostini et al. (2007) USA Observational Cohort Study •Multi centre—unspecified number of primary health clinics •Sample n = 756 ambulatory, English speaking adults aged 65 years and over •No new intervention—patients with current statin prescription: Lovastatin; Atorvastatin, pravastatin; simvastatin compared with non-statin users Baseline cholesterol level taken from medical record on nearest date before enrolment •Measures taken by interview at baseline and 1 year follow up •Measure: Center for Epidemiologic Studies Depression Scale (CES-D) Chronic statin use does not adversely affect depressive symptoms •Slight increase in depressive symptoms in older statin users (over 80) with > 3 co-morbidities •Statin users are prescribed more medications with mean average 6.6 versus 4.6 medications in non-statin users StrengthsCompares statin users to non-statin users •Adequate sample size •Comparison with control group •No exclusion for previous mood disorder, co-morbidity or polypharmacy •Data adjustment for co-morbidity, polypharmacy, smoking and alcohol use •Studies older patients with co-morbidity •Limitations Not an RCT •No comparison between statins •Limited generalisability to older, white, well-educated, male veterans •Does not test a new intervention •No adjustment made for co-morbidity diagnosed after start of trial •Follow up only once after 1 year •Mood questionnaires potentially ineffective in older men •Attrition not reported Strengths [40] Olson et al (2008) USA Retrospective reanalysis design 4 centres •Sample n = 954 women aged 18 or over having a clinical indicated angiogram for chest pain and/or myocardial ischaemia One retrospective measurement taken for cholesterol •Single measurements taken from previous study •Measures: Cook–Medley Questionnaire (hostility and aggression), Beck Depression Inventory (depression)> Aggression is greater in those taking LLDs •Depression and hostility is not greater in those taking LLDs •In a subgroup of those with low cholesterol levels, only those taking LLDs had greater aggression •Greater aggression also reported when only statin usage was considered StrengthsCompares statins with non-statin LLDs •Adequate sample size •Focuses on women due to gap in research •No exclusion for previous mood disorder •Limitations Not an RCT •Does not compare different statins •Limited generalisability to women undergoing angiogram •Excludes significant physical co-morbidity •Does not test an intervention •No adjustment for differing baseline characteristics •Draws data from a previous study almost 10 years ago •No outcome comparison over time Open in new tab Depression The papers reported conflicting evidence for an association between statins and depression. Four studies found no increase or reduction in depressive symptoms associated with statin usage37–40. A further study, distinct due to the older sample (older than 65 years), reported no increased depressive symptoms in the main study, however, subgroup analysis of patients older than 80 years and with greater than 3 co-morbidities found a slight increase in depression scores (+ 0.88 points; P = 0.10) to be associated with statin usage41. Another study42 found no mood alteration when using comparable data collection methods to other studies in this review. However, an additional ‘daily diary’ method of data collection revealed a statin-associated decrease in positive affect along with decreased ability to cope with negative everyday life events. A further study, distinct in its randomised controlled double-blind crossover design, suggested evidence of an association between statin usage and depression43 with depression found to be increased in those randomised to treatment with simvastatin regardless of age, BMI, a decrease in serum cholesterol or steroid hormonal levels. Finally, in contrast to other studies one observational cohort study with an extensive follow-up period suggested an association between continuous statin usage and decreased depression23. The positive effect on depression was found to be cumulative and did not occur in intermittent statin therapy. Furthermore, depression was not evident where there was non-statin anticholesterolaemic drug therapy and there was no correlation with a decrease in serum cholesterol levels. Anxiety Of the six papers which reported treatment effect on anxiety, five well-designed double-blind RCTs reported no alteration in anxiety levels37–39,42,43. In contrast to these findings, one study23 found a decrease in anxiety levels which was uniquely associated with the statin class of lipid-lowering medications. The positive effect on anxiety was once again reported to be cumulative in uninterrupted statin therapy and irrespective of serum cholesterol levels. Anger, hostility and aggression Six of the included papers reported on anger, hostility and/or aggression. Of these, three found no association between statin therapy and alteration in these mood states37–39. These studies were well-designed double-blind RCTs confirming good external validity29. All included sufficient follow-up time (6 months38; 3 years37; 4 years39) for side-effects to become apparent45 and a power calculation confirmed a sufficient and therefore credible sample size in all three studies28. Two of the studies reported increased aggression in association with lipid-lowering therapy. In a retrospective reanalysis of data from a previous study40, an association between lipid-lowering therapy and increased aggression was found in an all female sample clinically indicated for angiogram. A similar effect on hostility was not found. Subgroup analysis of women with the lowest serum cholesterol (LDL cholesterol < 100) revealed that higher aggression was only evident in those taking lipid-lowering drugs. Furthermore, of these, increased aggression was only found in those taking statins (84% of anticholesterolaemic drug use in the study). Hyyppa et al.43 found increased self-reported aggression to be associated with simvastatin therapy. However, no corresponding increase in aggression was noted in questionnaires completed by the partners of study participants. In a study of 606 adults with coronary artery disease23 an association between statin therapy and decreased hostility was found. The positive effect on hostility mirrors the study’s findings for depression and anxiety and is unique in this review. Discussion In the late 1980s, with an accumulation of research supporting the relationship between increased serum cholesterol and coronary artery disease, population-wide efforts to reduce hypercholesterolaemia began in earnest46. The ability of statins to reduce both risk and incidence of disease is not in question, however, this review highlights that the effect of statins on psychological health in terms of mood remains unclear. Potential methodological limitations of reviewed studies Design The double-blind RCT design featured in all but three of the included studies. Two of the remaining three studies were observational cohort studies23,41 and the last comprised a retrospective reanalysis of data from a previous study40. Whilst the lack of randomisation into treatment and control group may have introduced selection bias into these studies47, the methodologies were clear and comprehensive and the large sample size in each strengthened reliability and validity48. Only two of the included papers reported no side-effect37,39. The majority therefore provided some evidence of an association between statins and mood alteration. Whether these results reflect reality or design artefact is, however, unclear as the effect on mood may be attributable to a state of hypocholesterolaemia itself or the act of cholesterol lowering as opposed to being a side-effect of anticholesterolaemic drugs per se. Morales et al.42 found that, in spite of uniform treatment (simvastatin 20 mg/day), the decrease in positive affect was greatest for those with total post-treatment cholesterol in the lowest quartile (< 148 mg/dL). These findings support early suggestions that cholesterol lowering itself affects mood49. A contrasting study40, however, proposed that statins themselves alter mood as even in their subgroup of participants with the lowest serum cholesterol (LDL-C < 100), only those taking lipid-lowering drugs demonstrated increased aggression. The positive effect on mood reported by Young-Xu et al.23 was also found to be unrelated to serum cholesterol levels, further supporting the hypothesis that statins rather than cholesterol reduction affect mood. If the effect is drug-related, consideration must be given to whether all lipid-lowering drugs, only statins or indeed only certain statins affect mood. Statin class drugs differ in their ability to permeate the blood-brain barrier50. Unlike hydrophylic pravastatin, the lipophylic nature of simvastatin allows blood-brain barrier permeability which may in turn cause central nervous system-associated mood changes. Unfortunately, few trials have compared different lipid-lowering drugs with the majority focussing on one statin only. Whilst some have included a number of statins, only the effect of the group of drugs as a whole was investigated41. Another trial first found increased aggression associated with all anticholesterolaemic agents and subsequently reported the same finding when studying only statins40. However, this study failed to report outcomes from non-statin lipid-lowering drugs so that no comparison could be made. Another study23 compared lipid-lowering treatments and reported a greater decrease in depression, anxiety and hostility with statin usage than with non-statin anticholesterolaemic drugs leading Young-Xu et al. to assert that the greatest mood improvement was associated with the lipophylic statins. The lack of research which specifically compares different lipid-lowering drugs and the inconsistent findings of existing studies suggest that further research is needed. Sampling The inclusion of participants with histories of mental disorder or substance abuse could confound the findings31 so not surprisingly two studies excluded those prescribed with psychotropic medications38 and another42 excluded people with a history of psychiatric illness, impaired cognition (Mini Mental State Examination score < 24) and/or significant depressive symptoms (Center for Epidemiological Studies Depression scale (CES-D) score > 12). Whilst these attempts to control for confounding strengthened internal validity29, it is possible that those with a history of mental health problems may be more susceptible to statin-associated mood disturbance. However, mental health disorders such as depression and anxiety are common in society51, and their exclusion may significantly limit the generalisability of the findings31. A potential limitation of this review is the largely male samples of the included studies with two all male samples41,43 and three samples comprising 80% males23,37,39 despite random recruitment methods. However, as European-wide CVD mortality is slightly more prevalent in women (54%)52, these predominantly male samples are not representative. Having noted the lack of research on women, one study specifically recruited an all female sample and reported statin-associated increased aggression40. As the prevalence of treated depression in Britain is approximately three times higher in women than in men53, further investigation of statin-associated effect on mood specifically in the female sample is recommended. Information about the educational level and ethnicity of study participants was limited with the available evidence suggesting largely well-educated and predominantly white samples. Five studies23,38,40–42 included samples with a higher than average level of schooling54. And of the four studies which included data on ethnicity38,40–42, white participants comprised between 82 and 88% of the sample suggesting an under-representation of participants from ethnic minorities55. Under-representation of less educated and ethnic minority participants who tend to occupy the lower socioeconomic classes56,57 is a recognised problem in research samples58. Language barriers may discourage the inclusion of some ethnic minorities whilst those with less education may feel intimidated by a research process which they do not understand. This is particularly relevant in studies which assess the effect of statins on psychological health as both the incidence of hypercholesteralaemia and the risk of mood disturbance are greater in those from a lower socioeconomic background59,60. By recruiting their sample through the occupational health service of five industrial plants, Hyyppa et al.36 succeeded in studying a sample from the lower socioeconomic groups. Their findings of increased aggression and depression in association with Simvastatin therapy support the need for future research with good representation from all elements of society. It is well documented that altered mood, and in particular depression, is associated with old age61 although its identification remains problematic51 despite attempts to improve both the diagnosis and treatment of depression in older people62. With this in mind, the prescription of a drug which may lead to mood disturbance in an already susceptible population requires careful consideration. The evidence did not indicate a strong association between statin usage and age-related mood disturbances. However, the majority of the reviewed studies limited the recruitment of those over 75 years either explicitly or indirectly. Of the two studies with older samples, one41 found no adverse effect of statins on mood in the main study, but reported slightly increased depression scores in a subgroup of those over 80 year of age and another study42 of those over 65 years of age reported a statin-associated decrease in positive affect. Whilst these findings do not constitute strong evidence, they add weight to an early suggestion that decreased cholesterol in old age may increase the risk of depression19. Measurement All studies collected data by means of self-report questionnaires although the ability of questionnaires to accurately measure mood is questionable as they are only capable of capturing the mood of an individual at the time of their completion and are therefore not a good measure of mood change over time63. Muldoon et al.38, for example, asked participants to report on their mood in the past 6 months, a lengthy period which undoubtedly comprised many mood states. It could be for this reason that the study found no statin-associated effect, in particular if an affect occurs during the initial phase of the drug’s prescription. The predominantly middle-aged male sample in the included studies may also affect the data collected via self-report questionnaires with middle-aged males less likely to express emotion or admit to feelings of depression or anxiety64. The answers given on mood assessment questionnaires may therefore not be a true reflection of the participant’s mood despite all authors making claims for the validity and reliability of their tools. In spite of the limitations, self-report questionnaires are deemed better suited to the identification of subtle statin-associated changes in mood. Early studies which measured outcome by clinical diagnosis of mood disorder or the incidence of suicide were limited by the relatively rare incidence of such outcomes. Instead, the measurement tools utilised in this review may assist the earlier recognition and treatment of statin-associated mood disturbance. Limitations of this review It is recognised that the unobtainable papers (n = 18) could have impacted upon the findings of the review. However, their lack of citation throughout the searched literature suggests that they were not key papers in the field and the impact of their non-inclusion is therefore felt to be limited. Conclusion The contradictory findings of this review do not confirm that statin therapy adversely affects mood. However, the assumption that statins have no harmful effect on mood has not been proved. The review identifies the need for further RCTs comparing different lipid-lowering drugs in addition to investigating the correlation between mood disturbance and decreased serum cholesterol. Further research with older, female and lower socioeconomic samples is particularly recommended. Statins clearly offer substantial cardiovascular benefits and the contradictory findings of this review should not discourage appropriate statin administration. However, nurses have a duty of care to their patients which should be holistic and encompass both physical and psychological health65 and be alert to the potential risk of mood disturbance in the increasing number of patients receiving lipid-lowering therapy. Altered mood may impact negatively on physical health, for example, depression decreases survival rates following myocardial infarction66. Nurses should be ready to intervene in cases of mood disturbance, referring the patient for a medication and/or psychiatric review as appropriate. This review provides the basis for further enquiry regarding the undiagnosed side-effects of statins and their potential impact upon the quality of life of the low risk, mildly hypercholesterolaemic patient and their limited economic benefit in that population67. References 1. Roberts W . 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TI - The effects of statins on mood: a review of the literature
JF - European Journal of Cardiovascular Nursing
DO - 10.1016/j.ejcnurse.2010.08.008
DA - 2012-03-01
UR - https://www.deepdyve.com/lp/oxford-university-press/the-effects-of-statins-on-mood-a-review-of-the-literature-21LknnJjZa
SP - 85
EP - 96
VL - 11
IS - 1
DP - DeepDyve
ER -