Comment on: The relationship between statins and depression: a review of the literature

You et al. comprehensively reviewed the relationship between statins and depression. They concluded that statins may cause depressive symptoms, although they point out that a number of issues still need to be addressed [1]. Some comments may be of interest.

Some of the evidence supporting a possible association between statins and depression comes from fragmented reports and relatively small-scale studies with selected samples. Further, a recent meta-analysis involving seven controlled trials (n = 2105) found that statins had no significant effect on the development of depression compared with placebo, while statins were associated with statistically significant improvements in mood scores in the sensitivity analyses [2]. In addition, no significant differences were found when such effects were compared by long-term (3 – 4 years), intermediate (3 – 6 months) and short-term (4 weeks) use of statins. In 14 registration trials of pravastatin [3], the incidence of depression did not differ in 2485 patients treated with pravastatin or resin for up to 2 years; depression was reported in 1.6% (9/572) of resin-treated patients and 1.1% (21/1913) of patients receiving pravastatin. Further, a cohort study including 46,249 patients from 2003 to 2010 [4] created 6972 statin users and 6972 non-users by a propensity score-matched cohort design among the data of statin users (13,626 patients) and non-users (32,623 patients). In this study, the odds ratio of statin users for developing depression was only 1.02 (95% confidence interval: 0.94 – 1.11) [4]. The risk of developing depression was also similar after 4.5 years of follow up in this cohort between users and non-users of statin [4]. The safety and tolerability data from post-marketing surveillance may produce a more complete picture of the overall safety profile of a certain drug, compared with controlled trials. In this context, Bristol-Myers Squibb's post-marketing surveillance of over 1.5 million patients treated with pravastatin has shown only occasional reports of depression but no relation between pravastatin and depressive symptoms [3].

A number of epidemiological and preclinical studies have proven the potential benefit and role of omega-3 fatty acids (another lipid lowering agent) in the development and management of depression [5]. As for biological aspects, pravastatin was found to significantly increase plasma adiponectin levels, which has been involved in depressive-like behaviors and innovative therapeutic approach for depression [6]. An enhancement of the proteolytic cleavage of pro-brain-derived neurotrophic factor by statins has been suggested to be beneficial for treating depression and cognitive impairment [7]. Pravastatin is relatively hydrophilic and is not significantly metabolized by cytochrome P450 enzymes and is safe to use with antidepressants [8]. Further, the neurorestorative effect of some statins has been proposed to be mediated through activation of the Akt-mediated signaling pathway, subsequently upregulating the expression of growth factors as well as neurogenesis of the hippocampus, which should be beneficial in a recovery of cognitive function in patients with depression [9].

Statins may prevent metabolic syndrome associated with psychotropics [10] and may reduce the risk associated with metabolic syndrome. Maintaining safe antidepressant treatment is important since depression is a chronic and recurrent disease requiring longer-term treatment [11].

Finally, a recent US FDA Drug Safety Communication did not include a risk of developing or worsening of depression associated with statins [12].

Therefore, based on currently available evidence, it is hard to fully support the viewpoint of Dr You et al. Adequately powered well-designed trials are needed to conclude whether statins induce, worsen or even improve depression.

Declaration of interest

The authors state no conflict of interest and have received no payment in preparation of this manuscript.

Declaration of interest

The author states no conflict of interest. This work paper was supported by a grant from the Ministry of Health and Welfare (A120004).

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Author response

Hong You¹

Wei Lu^†1

Shuiping Zhao²

Zhiping Hu¹

Jinnan Zhang¹

^aXiangya No. 2 Hospital of Central South University, Department of Neurology, Changsha, Hunan 410011, China [phone]; [phone]; [email protected]

^bXiangya No. 2 Hospital of Central South University, Department of Cardiology, Changsha, Hunan 410011, China

We believe that professor Chiun Pae's view, which proposed that statins have no negative effects on depression, is very meaningful in some aspects, but not all [1]. Some evidence suggests that low cholesterol causes depression, by looking at the pathogenesis of depression [2]. Many clinical and biological studies had shown that statins could cause depression [3,4]. As we know, cholesterol plays an important role in the serotonin system, so statins that are used in lowering cholesterol may lead to the occurrence of depression [2]. Our article considers that statins could lead to depression by lowering cholesterol and that we should draw attention to this in clinical practice, especially for patients with depressive symptoms and/or low serum cholesterol levels [5].

Leichleitner et al. first recorded depressive symptoms in four hypercholesterolemic patients treated with pravastatin in 1992 [6]. Morales et al. found that simvastatin has statistically significant effects on the development of depressive symptoms in elderly volunteers (n = 756 age = ≥ 65 years) [4]. In a Finnish study of > 29,000 men, low levels of cholesterol were associated with major depressive disorder [7]. This study showed an independent association between low-density lipoprotein cholesterol (LDL-C) concentration and a high level of depressive symptoms in older patients. Additionally, a clinical study [8] including 28 drug-naive patients with major depression and an equal number of controls showed that serum LDL-C was 93.18 ± 25.17 mg/dL in depressives and 109.71 ± 28.76 mg/dL in controls; the difference was significant (p < 0.05). Recently, an observational study (n = 225) showed that higher depressive symptoms are modestly associated with lower level of LDL-C among young adult women [9]. In another observational study (n = 1040 women age = 65 years), the authors observed an increased prevalence of depression with low LDL-C and high-density lipoprotein cholesterol levels [10]. Taking into account these findings, we should not ignore the possibility that statins could lead to depression through excessive lowering of cholesterol levels.

Judging from the current literature, we know that some findings refute the evidence of negative effects of statins on psychological outcomes and provide some support for mood-related benefits. The known effects of statins on oxidative and inflammatory processes support the role of these processes in depression [11]. We also agree with these beneficial effects, but we believe that the use of statin might be a double-edged sword for some patients susceptible to detrimental psychological and behavioral outcomes associated with low cholesterol.