The impact of statins on psychological wellbeing : a systematic review and meta-analysis

Background : Cholesterol-lowering medications such as statins have anti-inflammatory and antioxidant properties, which may be beneficial for treating depression and improving mood. However, evidence regarding their effects remains inconsistent, with some studies reporting links to mood disturbances. We aimed to conduct a meta-analysis to determine the impact of statins on psychological wellbeing of individuals with or without hypercholesterolemia.

Methods : Articles were identified using medical, health, psychiatric and social science databases, evaluated for quality, and data were synthesized and analyzed in RevMan-5 software using a random effects model.

Results : The 7 randomized controlled trials included in the analysis represented 2,105 participants. A test for overall effect demonstrated no statistically significant differences in psychological wellbeing between participants receiving statins or a placebo (standardized mean difference (SMD) = -0.08, 95% CI -0.29 to 0.12; P = 0.42). Sensitivity analyses were conducted to separately analyze depression (n = 5) and mood (n = 2) outcomes; statins were associated with statistically significant improvements in mood scores (SMD = -0.43, 95% CI -0.61 to -0.24).

Conclusions : Our findings refute evidence of negative effects of statins on psychological outcomes, providing some support for mood-related benefits. Future studies could examine the effects of statins in depressed populations.

Growth inhibition of Candida species and Aspergillus fumigatus by statins

Statins are a class of drugs widely used for lowering high cholesterol levels through their action on 3-hydroxy-3-methylglutaryl-CoA reductase, a key enzyme in the synthesis of cholesterol. We studied the effects of two major statins, simvastatin and atorvastatin, on five Candida species and Aspergillus fumigatus. The statins strongly inhibited the growth of all species, except Candida krusei. Supplementation of Candida albicans and A. fumigatus with ergosterol or cholesterol in aerobic culture led to substantial recovery from the inhibition by statins, suggesting specificity of statins for the mevalonate synthesis pathway. Our findings suggest that the statins could have utility as antifungal agents and that fungal colonization could be affected in those on statin therapy.

Statins for the treatment of depression: a meta-analysis of randomized, double-blind, placebo-controlled trials

BACKGROUND: In epidemiological studies, statins appear to benefit mood, and there are now some randomized controlled trials examining the efficacy of statins. However, the role of statins in depression remains uncertain. Thus the aim of this paper was to assess the effect of statins on depressive symptoms by performing a meta-analysis of all double-blind, randomized, placebo controlled clinical trials (RCT) conducted in subjects with depression. METHODS: A systematic search was executed using PubMed and ClinicalTrials.gov in November 30th, 2015 for all double-blind, RCT of statins versus placebo in persons with depressive symptoms. Sixty-seven potential articles were identified through search of electronic databases, of those three met inclusion criteria and were included in the meta-analysis. The outcome measure was change in Hamilton Depression Rating Scale (HDRS) scores associated with statin use. A meta-analysis was conducted and standardized mean differences (SMDs) with 95% confidence intervals (CIs) were calculated. GRADE was used to assess study quality. RESULTS: The three articles included provided data on 165 participants with moderate to severe depression. Of these, 82 were randomized to statins as an adjuvant therapy to antidepressant treatment (i.e., citalopram or fluoxetine) and 83 to the placebo arm. All studies were double-blind RCTs, with a follow-up of 6-12 weeks. The statin agents evaluated were lovastatin, atorvastatin, and simvastatin. When compared to placebo, statins, as add-on to treatment as usual, largely improved depressive symptoms as assessed by the HDRS (SMD=-0.73, 95% IC -1.04 to -0.42, p<0.001, 3 between-group comparisons, n=165). No serious adverse effects were reported. CONCLUSIONS: Our results suggest that adjunctive treatment with statins could be useful for the treatment of depressive symptoms. Additional double-blind, randomised, placebo-controlled trials are necessary to settle the matter.

General practitioners' nutrition promotion among cardiac patients

General practitioners fall into three categories in their pursuit of dietary counselling: little involvement, or provider of referrals, or they have strong involvement. The barriers to dietary counselling are inadequate partnerships with dietitians, patients suffering multiple medical conditions and the view that HMG-CoA-reductase-inhibitors (statins) reduce the need for dietary change.

Significant challenges remain to achieve risk reduction targets for cardiovascular secondary prevention and diabetes

Objective: To examine population-level evidence treatment gaps for cardiovascular risk among rural patients with existing cardiovascular disease or diabetes.

Methods: Three population surveys were undertaken in the Greater Green Triangle region of southeastern Australia 2004-2006. Adults aged 25-84 yrs were randomly selected using age/sex stratified electoral role samples. A representative 1690 participants were recruited (48% participation rate). Anthropometric, clinical and self-administered questionnaire chronic disease risk data were collected in accordance with the WHO MONICA protocol. Detailed investigation of cardiovascular and diabetes history, key cardiovascular risk factors, medication use and health behaviours were included.

Results: After adjusting for age and sex, an estimated 12% (sample n=272) of the population had one or more of coronary heart disease, stroke, or diabetes. Blood pressure was at target (<130/80 mmHg) for 26% of these individuals, and 61% were treated with antihypertensive medications. Lipid targets were achieved by 17% for total cholesterol (<4 mmol/L), 18% for LDL cholesterol (<2 mmol/L), 77% for HDL cholesterol (>1.0 mmol/L) and 44% for triglycerides (<1.5 mmol/L); overall 6% achieved all four lipid targets and 60% reported use of lipid-lowering therapy, including 51% overall using statins. Ten percent were current smokers, and four in every five patients (82%) had suboptimal BMI (outside the range 18.5 - 25.0).

Conclusions: All participants with uncontrolled blood pressure and most with uncontrolled lipids should be taking medications. The magnitude of evidence treatment gaps suggests existing models of care need fundamental reform and renewed focus on prevention.

Statin use, bone mineral density, and fracture risk: Geelong Osteoporosis Study

Background Recent data suggest that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) decrease fracture risk and increase bone mineral density (BMD).

Methods This cross-sectional study is set in southeastern Australia. We evaluated the association between statin use, fracture risk, and BMD in 1375 women (573 with incident fractures and 802 without incident fracture, all drawn from the same community). Fractures were identified radiologically. Medication use and lifestyle factors were documented by questionnaire.

Results Unadjusted odds ratio for fracture associated with statin use was 0.40 (95% confidence interval [CI], 0.23-0.71). Adjusting for BMD at the femoral neck, spine, and whole body increased the odds ratio to 0.45 (95% CI, 0.25-0.80), 0.42 (95% CI, 0.24-0.75), and 0.43 (95% CI, 0.24-0.78), respectively. Adjusting for age, weight, concurrent medications, and lifestyle factors had no substantial effect on the odds ratio for fracture. Statin use was associated with a 3% greater adjusted BMD at the femoral neck (P = .08), and BMD tended to be greater at the spine and whole body but did not achieve statistical significance.

Conclusion The substantial 60% reduction in fracture risk associated with statin use is greater than would be expected from increases in BMD alone.

Improving the cost-effectiveness of cardiovascular disease prevention in Australia : a modelling study

Background : Cardiovascular disease is the leading cause of death worldwide. Like many countries, Australia is currently changing its guidelines for cardiovascular disease prevention from drug treatment for everyone with 'high blood pressure' or 'high cholesterol', to prevention based on a patient's absolute risk. In this research, we model cost-effectiveness of cardiovascular disease prevention with blood pressure and lipid drugs in Australia under three different scenarios: (1) the true current practice in Australia; (2) prevention as intended under the current guidelines; and (3) prevention according to proposed absolute risk levels. We consider the implications of changing to absolute risk-based cardiovascular disease prevention, for the health of the Australian people and for Government health sector expenditure over the long term.

Methods : We evaluate cost-effectiveness of statins, diuretics, ACE inhibitors, calcium channel blockers and beta-blockers, for Australian men and women, aged 35 to 84 years, who have never experienced a heart disease or stroke event. Epidemiological changes and health care costs are simulated by age and sex in a discrete time Markov model, to determine total impacts on population health and health sector costs over the lifetime, from which we derive cost-effectiveness ratios in 2008 Australian dollars per quality-adjusted life year.

Results : Cardiovascular disease prevention based on absolute risk is more cost-effective than prevention under the current guidelines based on single risk factor thresholds, and is more cost-effective than the current practice, which does not follow current clinical guidelines. Recommending blood pressure-lowering drugs to everyone with at least 5% absolute risk and statin drugs to everyone with at least 10% absolute risk, can achieve current levels of population health, while saving $5.4 billion for the Australian Government over the lifetime of the population. But savings could be as high as $7.1 billion if Australia could match the cheaper price of statin drugs in New Zealand.

Conclusions : Changing to absolute risk-based cardiovascular disease prevention is highly recommended for reducing health sector spending, but the Australian Government must also consider measures to reduce the cost of statin drugs, over and above the legislated price cuts of November 2010.

New drug targets in depression : inflammatory, cell-mediated immune, oxidative and nitrosative stress, mitochondrial, antioxidant, and neuroprogressive pathways. And new drug candidates—Nrf2 activators and GSK-3 inhibitors

This paper reviews new drug targets in the treatment of depression and new drug candidates to treat depression. Depression is characterized by aberrations in six intertwined pathways: (1) inflammatory pathways as indicated by increased levels of proinflammatory cytokines, e.g. interleukin-1 (IL-1), IL-6, and tumour necrosis factor α. (2) Activation of cell-mediated immune pathways as indicated by an increased production of interferon γ and neopterin. (3) Increased reactive oxygen and nitrogen species and damage by oxidative and nitrosative stress (O&NS), including lipid peroxidation, damage to DNA, proteins and mitochondria. (4) Lowered levels of key antioxidants, such as coenzyme Q10, zinc, vitamin E, glutathione, and glutathione peroxidase. (5) Damage to mitochondria and mitochondrial DNA and reduced activity of respiratory chain enzymes and adenosine triphosphate production. (6) Neuroprogression, which is the progressive process of neurodegeneration, apoptosis, and reduced neurogenesis and neuronal plasticity, phenomena that are probably caused by inflammation and O&NS. Antidepressants tend to normalize the above six pathways. Targeting these pathways has the potential to yield antidepressant effects, e.g. using cytokine antagonists, minocycline, Cox-2 inhibitors, statins, acetylsalicylic acid, ketamine, ω3 poly-unsaturated fatty acids, antioxidants, and neurotrophic factors. These six pathways offer new, pathophysiologically guided drug targets suggesting that novel therapies could be developed that target these six pathways simultaneously. Both nuclear factor (erythroid-derived 2)-like 2 (Nrf2) activators and glycogen synthase kinase-3 (GSK-3) inhibitors target the six above-mentioned pathways. GSK-3 inhibitors have antidepressant effects in animal models of depression. Nrf2 activators and GSK-3 inhibitors have the potential to be advanced to phase-2 clinical trials to examine whether they augment the efficacy of antidepressants or are useful as monotherapy.

Lovastatin for the adjunctive treatment of schizophrenia: a preliminary randomized double-blind placebo-controlled trial.

While statins target many of the pathways to neuroprogression in schizophrenia, the safety and efficacy of statins for treating schizophrenia has never been examined. This is an 8-week randomized double blind controlled clinical trial examining the efficacy and safety of adjunctive lovastatin (20 mg/day) treatment or placebo for people with schizophrenia. The baseline characteristics of the two groups were not different. Endpoint changes in Positive and Negative Syndrome Scale (PANSS) total and subscale scores did not differ between the two groups. However there was a significant difference between the doses of risperidone used in the two groups. The mean dose in the lovastatin and placebo groups were 4.8(1.8) and 3.4(1.4) mg/day, respectively (P<.03). No serious adverse events were reported. Slowness of movements, muscle rigidity, increased appetite, and decreased energy were the most common adverse effects, and these rates did not differ between the two groups. This study failed to demonstrate a benefit of lovastatin on symptoms of schizophrenia. This combination was well tolerated. However, a higher dosage of risperidone was used for treating the disorder in those taking concomitant lovastatin compared to placebo.

Current and emerging therapeutic strategies for preventing inflammation and aggrecanase-mediated cartilage destruction in arthritis

Arthritis is a multifactorial disease for which current therapeutic intervention with high efficacy remains challenging. Arthritis predominately affects articular joints, and cartilage deterioration and inflammation are key characteristics. Current therapeutics targeting inflammatory responses often cause severe side effects in patients because of the systemic inhibition of cytokines or other global immunosuppressive activities. Furthermore, a lack of primary response or failure to sustain a response to treatment through acquired drug resistance is an ongoing concern. Nevertheless, treatments such as disease-modifying anti-rheumatic drugs, biological agents, and corticosteroids have revealed promising outcomes by decreasing pain and inflammation in patients and in some cases reducing radiographic progression of the disease. Emerging and anecdotal therapeutics with anti-inflammatory activity, alongside specific inhibitors of the A Disintegrin-like And Metalloproteinase domain with Thrombospondin-1 repeats (ADAMTS) cartilage-degrading aggrecanases, provide promising additions to current arthritis treatment strategies. Thus, it is paramount that treatment strategies be optimized to increase efficacy, reduce debilitating side effects, and improve the quality of life of patients with arthritis. Here, we review the current strategies that attempt to slow or halt the progression of osteoarthritis and rheumatoid arthritis, providing an up-to-date summary of pharmaceutical treatment strategies and side effects. Importantly, we highlight their potential to indirectly regulate ADAMTS aggrecanase activity through their targeting of inflammatory mediators, thus providing insight into a mechanism by which they might inhibit cartilage destruction to slow or halt radiographic progression of the disease. We also contrast these with anecdotal or experimental administration of statins that could equally regulate ADAMTS aggrecanase activity and are available to arthritis sufferers worldwide. Finally, we review the current literature regarding the development of synthetic inhibitors directed toward the aggrecanases ADAMTS4 and ADAMTS5, a strategy that might directly inhibit cartilage destruction and restore joint function in both rheumatoid arthritis and osteoarthritis.

Statin use and risk of depression: a Swedish national cohort study

Background : Statin medications, used to prevent heart disease by reducing cholesterol, also reduce inflammation and protect against oxidative damage. As inflammation and oxidative stress occur in depression, there is interest in their potential to reduce depression risk. We investigated whether use of statin medications was associated with a change in the risk of developing depression in a very large Swedish national cohort (n¿=¿4,607,990).MethodsNational register data for adults ¿40yr was analyzed to obtain information about depression diagnoses and prescriptions of statin medications between 2006 and 2008. Associations were tested using logistic regression.ResultsUse of any statin was shown to reduce the odds of depression by 8% compared to individuals not using statin medications (OR¿=¿0.92, 95% CI, 0.89-0.96; p¿<¿0.001). Simvastatin had a protective effect (OR¿=¿0.93, 95% CI, 0.89-0.97; p¿=¿0.001), whereas atorvastatin was associated with increased risk of depression (OR¿=¿1.11, 95% CI, 1.01-1.22; p¿=¿0.032). There was a stepwise decrease in odds ratio with increasing age (OR¿¿¿40 years¿=¿0.95, OR¿¿¿50 years¿=¿0.91, OR¿¿¿60 years¿=¿0.85, OR¿¿¿70 years¿=¿0.81).ConclusionsThe use of any statin was associated with a reduction in risk of depression in individuals over the age of 40. Clarification of the strength of these protective effects, the clinical relevance of these effects and determination of which statins are most effective is needed.