Review
Statins use and risk of depression: A systematic review and meta-analysis

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Abstract

Importance

Statin use has been associated with depression; however studies of the association between statin use and depression have yielded mixed results.

Objective

To determine whether statin use is associated with depression and to evaluate the evidence supporting this association.

Data sources

Ovid MEDLINE In-Process & Other Non-Indexed Citations, Ovid MEDLINE, EMBASE, PsycInfo, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus were searched through December 28, 2012.

Study selection

We included studies that evaluated exposure to statins, reported the development of depression, and relative risks or odds ratios (ORs) or provided data for their estimation. Two reviewers screened 981 abstracts independently using a standardized form, reviewed full text of 59 selected articles, and included 7 studies in this metaanalysis.

Data extraction and synthesis

Study design, statin exposure, development of depression, and study quality were extracted by 2 independent reviewers. A pooled OR with 95% confidence interval (CI) was estimated using the random-effects model and heterogeneity was assessed using Cochran's Q test and the I2 statistic.

Results

Seven observational studies (4 cohort, 2 nested case-control, and 1 cross-sectional) from 5 countries enrolling 9187 patients were included. Statin users were 32% less likely to develop depression than nonusers (adjusted OR, 0.68; 95% CI, 0.520.89). Modest heterogeneity was observed between the studies (I2=55%, P=0.01), which could be accounted for by one study, exclusion of which removed the heterogeneity (P=0.40, I2=2%) and further strengthened the antidepressant effect of statin (adjusted OR, 0.63; 95% CI, 0.430.93). Heterogeneity could not be explained by study design or study population. The quality of supporting evidence was fair.

Conclusions and relevance

This systematic review and meta-analysis suggests that statin use is associated with lower risk for depression. However, higher-quality studies are needed to confirm the magnitude of this association.

Introduction

Statins (hydroxymethylglutaryl co-A reductase inhibitors) play a beneficial role in the primary and secondary prevention of coronary artery disease (CAD), including among patients with average cholesterol level (Benito-Len et al., 2010, Carney and Freedland, 2008, Chan et al., 2000). Statins also have reported benefits in various other disorders including Alzheime's disease (Cochran, 1954) and other dementia, stroke, macular degeneration and osteoporosis (Cohen, 1960, Davey Smith and Pekkanen, 1992, DerSimonian and Laird, 1986, Downs et al., 1993, Downs et al., 1998, Engelberg, 1992, Freedman et al., 1995, Goldberg et al., 1998). This suggests that statins may have advantages beyond their effect on CAD and cholesterol. As statin use expands, concerns have been raised about possible negative consequences, including increased risk of non-cardiac death and a possible association of low serum cholesterol with antisocial personality, violent behavior, suicide, and aggressive conduct (Hall et al., 2001; Harrison and Ashton, 1994; Higgins et al., 2003; Hillbrand et al., 1995; Jick et al., 2000; Keech et al., 1994; Lindberg and Hallas, 1998; Marx, 2001). Given these concerns regarding statins and behavioral issues, several studies have attempted to determine a connection between statins and depression. A postulated mechanism for positive association of statins with depression relates to low plasma cholesterol leading to decreased membrane cholesterol in the brain, which could affect central neurotransmitter function and lower serotonergic activity, leading to depression (Harrison and Ashton, 1994). Possible direct effect of statins on brain functions could also be responsible for depression (Harrison and Ashton, 1994). Remission rates for elderly depressed patients treated with antidepressants have been shown to be lower when the same patients are taking cholesterol lowering medications (McAlister et al., 2001). This evidence further supports the positive association between the use of statins and depression.

On the other hand, protective effect of statins against depression has also been reported (Meier et al., 2000, Moher et al., 2009). In addition, several studies report no association between depression and statins (Muldoon, 1994, Muldoon et al., 1990, ONeil et al., 2012, Oliver, 1992, Otte et al., 2012, Pasco et al., 2010). Thus, the association of statins with depression has remained uncertain. A recent review by While et al. found conflicting evidence for the association of statins with mood, however they could not reach a definite conclusion and they did not perform a meta-analysis (Pedersen et al., 1996).

Therefore, we performed a systematic review and meta-analysis of all studies evaluating the association between statin use and depression, to quantify the magnitude of this association and appraise the quality of the supporting evidence.

Section snippets

Methods

This systematic review and meta-analysis is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) stat0ement guidelines (Sacks et al., 1996).

Study selection

The initial search identified 979 articles; two additional articles were identified through the references search of relevant articles. No additional articles were identified from the search of conference proceedings. Preliminary screening of titles and abstracts excluded 922 articles (Fig. 1) with an interobserver agreement of kappa=0.94 (95% CI 0.890.98). Full text review of the remaining 59 articles was done by same two reviewers in parallel, resulting in inclusion of 7 studies in the final

Discussion

This meta-analysis based on a systematic review of current evidence drawn from seven observational studies with good quality enrolling 9187 participants suggests that statins have a protective effect against depression. These studies were conducted in diverse populations across multiple countries making the results more generalizable.

Our findings are consistent with a previous meta-analysis of clinical trials that evaluated the impact of statins on psychosocial wellbeing (Wells Gas et al., 2013

Role of funding source

This work was supported by CTSA grant UL1 TR000135 from the National Center for Advancing Translational Sciences, a component of the National Institutes of Health (NIH). The contents of this article are solely the responsibility of the authors and do not necessarily represent the official view of the NIH.

Conflict of interest

None of the authors have any conflict of interest.

Acknowledgment

We thank Patricia J. Erwin, Assistant Professor of Medical Education, College of Medicine, Mayo Clinic, Rochester, MN (librarian with extensive expertise in literature search) for helping with literature search.

Ajay K. Parsaik has full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

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