Statins: Neurobiological underpinnings and mechanisms in mood disorders
Introduction
Statins (3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors) are among the most prescribed medications worldwide. Understanding the extent of their biological effects and clinical utility is thus critical. Statin medications are used for primary and secondary prevention of cardiovascular diseases due to their effectiveness in reducing cardiovascular-related morbidity and mortality (Cholesterol Treatment Trialists et al., 2012; Mills et al., 2008). They act by attenuating low density lipoprotein (LDL)-cholesterol, as well as lowering systemic inflammation, leading to stabilizing effects on coronary plaques and even modest regression of atheroma (Ridker et al., 2005).
Initially, statin use was reported to be associated with increases in mood disturbances (e.g., aggression, impulsivity) and suicidal deaths – despite efficacy for decreasing rates of both coronary heart disease related and total mortality (Ridker et al., 2005; Zureik et al., 1996). Negative mood states such as anger and depression, as well as violent acts directed at others or the self, were attributed to the role statins play in reducing evoked potential indexed brain serotonin (Park et al., 2014). More recent and rigorous evidence in contrast suggests that generally, statins do not provoke violence, nor do they confer increased risk for depression (Dave et al., 2018; Leppien et al., 2018; Molero et al., 2020). Rather, statins may exert beneficial effects for neuropsychiatric disorders (Kim et al., 2019; LaRosa et al., 2007; Muldoon et al., 2001). For example, meta-analyses of randomised controlled trials (RCTs) investigating the effects of statins on psychological outcomes indicate that statins do not worsen depressive symptoms in non-depressed subjects. In fact, improvements in depressive symptoms have been noted, particularly in patients with clinical depression (Kohler-Forsberg et al., 2020; O’Neil et al., 2012; Yatham et al., 2019). This is consistent with a meta-analysis of observational studies reporting statin use reduced the risk of depression (Parsaik et al., 2014). A handful of small methodologically limited trials including participants with major depressive disorder (MDD) have reported antidepressant-like properties of statins when administered concurrently with selective serotonin reuptake inhibitors (SSRI) (Ghanizadeh and Hedayati, 2013; Gougol et al., 2015; Haghighi et al., 2014; Kim et al., 2015b).
Statins can be categorised in a several ways, based on their lipophilicity, bioavailability, chemical structure, derivatives, metabolism, or their potency. Of the statins in clinical use, some are relatively hydrophilic (rosuvastatin, pravastatin), and some are relatively lipophilic (atorvastatin, simvastatin, fluvastatin lovastatin, pitavastatin). The lipophilicity of these medications has implications for factors such as membrane permeability and absorption, as well as toxicity. Simvastatin and lovastatin for example cross membranes via passive diffusion, whereas rosuvastatin and pravastatin on the other hand require active transport. Statins also can be divided by their potency, wherein atorvastatin and rosuvastatin are considered more potent, being able to reduce LDL-cholesterol by over 50 %. Comparatively the remaining statins have lower potency, managing 30–50% reductions (Oesterle et al., 2017; Stone et al., 2013). For detailed discussion regarding the classification of statins, see (Sirtori, 2014).
Importantly, independent of their lipid-lowering effects, statins have a variety of additional pleiotropic effects potentially relevant to the treatment of mood disorder pathophysiology. For example, statins have been reported to alter hypothalamus–pituitary–adrenal (HPA) axis activity, neurotransmitter systems, neurotrophins and neuroplastic processes, levels of oxidative and nitrosative stress (O&NS), as well as influence the neuro-immune axis (Dantzer et al., 2011; Eyre and Baune, 2012; Green et al., 2011; Hashimoto, 2009; Pace and Miller, 2009). In this review, we explore the mechanisms buttressing the potential use of statins in mood disorders. Relevant epidemiological and clinical findings are examined, with an emphasis on how statins may address various dysfunctions within the central nervous system (CNS) that are relevant to psychiatric disorders. Preclinical evidence is also leveraged to support mechanistic discussion. We begin by reviewing the paradigm of disturbed cholesterol homeostasis in patients suffering from mood disorders. The implication of immune-inflammatory and oxidative stress pathways in the pathophysiology of mood disorders is next addressed, before we discuss the broad putative effects that statins on these systems. Finally, important considerations including adverse events, and questions of effect magnitude, dose and drug selection and individual appropriateness of treatment are raised.
Section snippets
Cholesterol in the context of mood disorder pathophysiology
A range of cholesterol markers, including total cholesterol, triglycerides, high-density lipoprotein (HDL)-cholesterol and LDL-cholesterol, have been explored in depression (Parekh et al., 2017). Cellular uptake of cholesterol from the bloodstream is dependent on lipoproteins. For this reason, many studies have chosen to focus on HDL and LDL. However, likely due to methodological differences in study design (e.g., cross-sectional, prospective cohort, or interventional) and sample selection
Statins, inhibition of glutamate excitotoxicity and lipid raft mediated oxidative signalling
A major neurobiological mechanism of statin action may be due to cholesterol levels and their role in maintaining the structure and function of membrane lipid rafts. Depleted levels of this sterol can lead to synaptic dysfunction as lipid rafts are crucial for neurotransmitter release (Pristera and Okuse, 2012; Sebastiao et al., 2013). Statins effects on membrane lipid rafts are mediated via their impact on cholesterol synthesis and post-transcription modifications of key structural and
Mechanisms underpinning the beneficial effects of statins on oxidative stress levels
Preclinical evidence suggests that statins exert their antioxidative effects in several ways. Rosuvastatin inhibits the Rho kinase pathway, which is widely distributed in the central nervous system (Liu et al., 2012). In cell culture and murine models, inhibition of Rho kinase provides cellular neuroprotection (Tonges et al., 2012). An alternative action involves the inhibition of the small GTPase RAC-1 with a subsequent reduction in NADPH oxidase activity, observed in human and animal studies (
Statins and T cell homeostasis
Human and animal studies show statin therapy exerts a favourable T helper 17 cell/ regulatory T cell (Th17/Treg) balance by inhibiting the differentiation of naive CD4 + T cells down the Th17 pathway and favouring the production of Tregs (Greenwood and Mason, 2007; Ulivieri and Baldari, 2014; van Leuven et al., 2011; Xu et al., 2014). While much of the evidence regarding Th17 differentiation is indirect, there is accumulating human studies demonstrating increased levels and/or activity of Tregs
Statins, stimulation of neurogenesis and inhibition of neuroprogression
Statins promote neurogenesis, further promoting its potential as a novel therapeutic target for many potentially neuroprogressive disorders where impaired neurogenesis is a characteristic feature (Maes et al., 2012a). For example, animal studies using experimentally induced traumatic brain injury suggest that statins stimulate adult neurogenesis with a positive effect on cognitive functions and general neuro-restoration (Wu et al., 2008). The stimulatory effect on neural regeneration appears to
Statins and mood related symptoms
A meta-analysis comprising of seven observational studies (4 cohort, 2 nested case-control, and 1 cross-sectional) with 9187 participants explored the use of statins in depression (Parsaik et al., 2014). Statin users were less likely to develop depression than non-users as well as exhibit higher mood scores, in what was a modestly heterogeneous dataset. However, in this meta-analysis patient-level characteristics could not be accounted for, and the studies included differed both on scales used,
Potential adverse effects of statin therapy
Statins have been reported to cause side-effects including fatigue, myopathies and neurocognitive defects. These side-effects are thought to be, in part, related to the effects of statins on mevalonic acid, the precursor of coenzyme Q10, through the inhibition of HMG-CoA reductase (Deichmann et al., 2010). Furthermore, statins lower coenzyme Q10 concentrations, an antioxidant that has anti-inflammatory effects, in serum and muscle tissues (Deichmann et al., 2010). This may be important for
Questions of drug selection, dose, and effect
Much of the discussion in this review surrounds the pleiotropic properties of statins and the implications for their putative therapeutic effects. To this end we propose that these effects, in concert, may prove useful for the treatment of mood disorders in some individuals. However, there is much work to be done to validate this hypothesis before statins can be added to the proverbial psychiatric toolkit.
First, there is the problem of clinical effect. While some of the biochemical effects of
Conclusion
Statins are widely prescribed for cardiovascular indications because of their lipid-lowering properties. This review summarised the multiple mechanisms by which statins may influence the neurological and psychiatric substrates of mood disorders. While early methodologically limited studies reported psychiatric risks in relation to statin use, more recent and rigorous evidence suggests that statins may have properties useful for the treatment of mood disorders, supported by early clinical trial
Author contributions
Initial literature search and draft manuscript prepared by IB with guidance from MB. All subsequent manuscript drafts were prepared by AJW and YK. RR and AJW created descriptive figures. Revisions and edits were provided by RR, SD, GM, AN, MM, BSF, OMD, LJW, HE, SWK, SZ, AFC and MB.
Funding and conflicts
AJW has received funding support from the Trisno Family Gift, and Deakin University. OMD has received grant support from the Brain and Behavior Foundation, Simons Autism Foundation, Stanley Medical Research Institute, Deakin University, Lilly, NHMRC and ASBDD/Servier. She has also received in kind support from BioMedica Nutraceuticals, NutritionCare and Bioceuticals. MB has received Grant/Research Support from the NIH, Cooperative Research Centre, Simons Autism Foundation, Cancer Council of
Acknowledgements
The authors wish to dedicate this manuscript to the memory of Dr Igor Borissiouk. AJW is supported by a Trisno Family Research Fellowship, Deakin University. OMD is supported by an R.D. Wright NHMRC Biomedical Career Development Fellowship (1145634). MB is supported by a NHMRC Senior Principal Research Fellowship (1156072). LJW is supported by a NHMRC Emerging Research Fellowship (1174060).
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