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BY 4.0 license Open Access Published by De Gruyter September 23, 2021

Lipophilic vs. hydrophilic statins and psychiatric hospitalizations and emergency room visits in US Veterans with schizophrenia and bipolar disorder

Teodor T. Postolache EMAIL logo , Deborah R. Medoff , Clayton H. Brown , Li Juan Fang , Sanjaya K. Upadhyaya , Christopher A. Lowry , Michael Miller and Julie A. Kreyenbuhl
From the journal Pteridines

Abstract

Objective

Psychiatric hospitalizations and emergency department (ED) visits are costly, stigmatizing, and often ineffective. Given the immune and kynurenine activation in bipolar disorder (BD) and schizophrenia, as well as the immune-modulatory effects of statins, we aimed to compare the relative risk (RRs) of psychiatric hospitalizations and ED visits between individuals prescribed lipophilic vs. hydrophilic statins vs. no statins. We hypothesized (a) reduced rates of hospitalization and ER utilization with statins versus no statins and (b) differences in outcomes between statins, as lipophilia increases the capability to penetrate the blood–brain barrier with potentially beneficial neuroimmune, antioxidant, neuroprotective, neurotrophic, and endothelial stabilizing effects, and, in contrast, potentially detrimental decreases in brain cholesterol concentrations leading to serotoninergic dysfunction, changes in membrane lipid composition, thus affecting ion channels and receptors.

Methods

We used VA service utilization data from October 1, 2010 to September 30, 2015. The RRs for psychiatric hospitalization and ED visits, were estimated using robust Poisson regression analyses. The number of individuals analyzed was 683,129.

Results

Individuals with schizophrenia and BD who received prescriptions for either lipophilic or hydrophilic statins had a lower RR of psychiatric hospitalization or ED visits relative to nonstatin controls. Hydrophilic statins were significantly associated with lower RRs of psychiatric hospitalization but not of ED visits, compared to lipophilic statins.

Conclusion

The reduction in psychiatric hospitalizations in statin users (vs. nonusers) should be interpreted cautiously, as it carries a high risk of confounding by indication. While the lower RR of psychiatric hospitalizations in hydrophilic statins relative to the lipophilic statins is relatively bias free, the finding bears replication in a specifically designed study. If replicated, important clinical implications for personalizing statin treatment in patients with mental illness, investigating add-on statins for improved therapeutic control, and mechanistic exploration for identifying new treatment targets are natural next steps.

1 Introduction

1.1 Psychiatric hospitalizations and emergency room visits

Psychiatric hospitalizations represent markers of instability in severe mental illness and of insufficient therapeutic control, and are economically burdensome and stigmatizing. Even if multifactorial, they are most commonly driven by dangerousness to self or others and psychotic decompensation combined with the lack of social support in the community [1]. Inpatient hospitalization often fails to fulfill its main rationale, suicide risk management, as the discharge from the inpatient unit brings with it a substantially elevated potential for suicidal behavior [2,3]. In addition to psychiatric inpatient hospitalization, the use of Psychiatry Emergency Departments (ED) in the United States (US) is responsible for substantially increasing costs of health care [4,5] and diverting funds from services that would be expected to have a potentially more impactful contribution to quality care and preventative services. This is particularly true for the care of US Veterans, considering that the Veterans Health Administration (VHA) serves a population with considerable mental health needs [6] and has steeply increasing costs [7]. The top 10% of utilizers of psychiatric inpatient [8] and emergency services [9] are responsible for a disproportionally high share of healthcare costs. In the VHA system, understanding the clinical, social, and economic factors driving the utilization of psychiatric emergency services has relied on the availability and the analysis of administrative data [10,11] and has identified severe mental illness, personality disorders, substance use disorders, utilization of detox services, and homelessness as dominant predictive variables [12,13,14]. All in all, it is common knowledge for anyone who either worked or studied psychiatric emergency services that the reason for psychiatric hospitalization is the evaluation and management of acute suicide risk [2]. Thus, to a certain degree, psychiatric hospitalization also serves as a proxy measure of suicide risk. While important everywhere, in US Veterans, in particular, death by suicide and its prevention are the indisputable #1 priority. According to the latest available yearly report (2020), the 2018 age- and gender-adjusted rate of suicide in US Veterans was 27.5 per 100,000, 50% higher than in the US general population, as it has been each year since 2013–2014 [15]. In Veterans with mental health or substance use disorders, the 2018 rate was significantly twice, at 57.2 per 100,000. More than 17 Veterans are prematurely lost to suicide each day, with guns being the lethal means for 41.9% of female Veteran suicides and 69.4% of male Veteran suicide deaths.

1.2 Medications for medical conditions affect psychiatric condition

Comorbidity with medical illness often leads to worsening of the course of mental illness. However, there is a potential of the medical treatment per se to worsen mental health, directly (e.g., systemic corticosteroids decompensating mood disorders) or through interactions with psychiatric medication (e.g., thiazide diuretics for hypertension dramatically increasing lithium serum levels and causing toxicity in patients with bipolar disorder, or the commonly prescribed seizure medication phenytoin lowering the levels of clozapine in patients with schizophrenia and inducing a recurrence or exacerbation of psychosis).

Yet, there are circumstances when a specific medical treatment could have a beneficial effect on mental health. Examples include beta-blockers for anxiety, certain calcium blockers as mood stabilizers, certain alpha-adrenergic blockers on nightmares (prazosin), and others.

1.3 Statins

1.3.1 Pleiotropic effects

Statins, one of the most prescribed groups of medications worldwide, have been increasingly recognized as having therapeutic value for a variety of conditions beyond their original metabolic and cardiovascular indication [16]. Early, when the main data were anecdotal and observational, there were concerns that statin may worsen mood and cognition and have a negative impact on neuropsychiatric conditions and potentially elevate the suicide risk via the association between very low levels of serum cholesterol and suicide. With the emergence of case-control, longitudinal, and especially randomized controlled studies and their meta-analyses, the opposite picture emerged, i.e., that statins as a group are cognitively, affectively, and behaviorally safe and that they show beneficial effects in the treatment of mood disorders, schizophrenia, and cognitive disorders. These positive effects appear to be based on statins’ pleiotropic effects including multiple immune regulatory actions and antioxidant properties [17,18], as well as endothelial stabilizing [19] and neuroprotective effects [20,21]. Statins reduce NADPH oxidase and superoxide generation, inhibit the negative regulation of nitric oxide, increase free radical scavenging, decrease inflammatory cell transmigration from blood to tissue, inhibit the NLRP3 inflammasome, and reduce metalloproteinase expression [22,23,24,25,26,27]. Notably, evidence also suggests that statins facilitate PI3K-Akt signaling [28,29] and crosstalk with peroxisome proliferator-activated receptor (PPAR) signaling [30]. In addition, within the brain, statins are potent inducers of axonal and neurite outgrowth; in fact, among more than 50,000 small molecules previously implicated in axonal outgrowth, statins were the most effective [31]. Activation of the Akt signal transduction and RhoA prenylation underlie the statin-dependent neurite outgrowthn, which may account for the effects of statins to promote structural repair of injury and to reduce excitotoxicity, leading to the establishment, and maintenance of short- and long-distance connectivity with following injury. Consistently, high-dose simvastatin, a highly lipophilic statin, leads to less brain atrophy than a placebo-control group using serial volumetric MRIs in patients with the prototypical autoimmune disease of the brain-multiple sclerosis (MS).

1.3.2 Statins are beneficial for medical conditions characterized by inflammation

Statins have favorable long-term effects in individuals with medical conditions characterized by increased inflammation, both in medical conditions with increased inflammation primarily within the brain and in medical conditions with increased inflammation primarily in the periphery. For instance, sustained statin pretreatment and continuation lead to decreased mortality following traumatic brain injury (TBI; a condition in which inflammation plays a strong dual role of providing surveillance and removal of necrotic tissue, and also, being a negative prognostic indicator and a local mediator of pathophysiology leading to prolonged symptomatology, delayed healing, and limited functional recovery), as well as a more rapid hospitalization discharge, decreased depression post-TBI, and improved functional recovery at 12 months post-injury [32]. In patients with allergies, statin use is associated with a decreased risk of asthma-related ED visits [33,34] and/or hospitalizations [33]. Statins have also demonstrated benefit across autoimmune conditions, particularly, in MS [35].

1.3.3 Inflammation and immune-mediated conditions – links with mental illness and suicidal behavior

The involvement of inflammation in mental illness [36], including schizophrenia [37,38,39,40], bipolar disorder [41], and suicidal behavior [42,43,44,45], has been increasingly recognized. For instance, individuals with schizophrenia have a peripheral blood elevation of interleukin (IL) 6, IL-1β, and transforming growth factor-β1 (TFG-β1) [28], and, centrally, have molecular and visual markers of microglia activation relative to healthy controls [29], leading to ongoing vulnerability to immunological challenges and psychological stress. Immune-mediated clinical conditions implicated in schizophrenia have included infections, autoimmune disease, and atopy [46]. Similarly, suicidal behavior – a common driver of ED visits and hospitalizations – has also been associated with infections, with either specific microbial agents, such as Toxoplasma gondii, [47,48,49,50,51] or nonspecific microbial agents [52,53], allergy [54], and allergen exposure [55,56,57]. As illustrated in both preclinical and clinical studies, statins manifest a potent antimicrobial action across a broad spectrum of intracellular pathogens, including viruses, bacteria, protozoa, and fungi, interfering with the host mevalonate pathways and compromising the microbial immune evasion. Statin administration prolongs survival in certain infectious diseases by protecting from the overly intense and prolonged immune response, in addition to promoting host defense [58].

1.3.4 Statins in depression

Given the considerable overlap among elements of the immune, oxidative stress, excitotoxic, endothelial, and immune regulatory dysfunction in severe mental illness and reversal of these effects with statins, promising reports on experimental/animal models and early clinical data using statins for augmentation of classical psychotropic agents became increasingly attractive. While heterogenous and far from definitive, increasingly compelling data exist in support of with distinct clinical and physiopathological benefits with of the use of statins; with increasingly sophisticated and well-sized studies, the earlier concerns about potentially major negative effects of statins are slowly receding. For example, awareness of successful augmentation of antidepressant effects in major depression (MD) by statins begins to emerge, starting with a small meta-analysis [59] (3 studies on 165 participants), followed by a meta-analysis of 36 randomized placebo-controlled studies of anti-inflammatory add-on interventions including 7 randomized placebo-controlled studies on 1,576 participants [60]. This was further confirmed by a large meta-analysis of multiple anti-inflammatory approaches by Bai et al., including 30 studies, and 1,610 participants, including 3 randomized controlled trials of statins with 166 participants [61]. In the most recent meta-analysis of randomized clinical trials on 5 studies and 389 participants, De Giorgi et al. reported significant benefits of add-on statins at 8 and 12 weeks of treatment. In comparing statins, simvastatin, the most lipophilic compound, demonstrated a stronger antidepressant capability than atorvastatin [62]. This was consistent with a previous study on the antidepressant effect of statin in post coronary artery bypass graft with mild-moderate clinical depression, demonstrating a greater efficacy of simvastatin over atorvastatin [63].

1.3.5 Statins in schizophrenia

In schizophrenia, a meta-analysis of 5 RCTs (with 236 adult participants with schizophrenia, neuroleptic treated) found improvement in positive and negative symptom scores with an add-on statin vs. placebo [64]. A larger meta-analysis (70 studies, 4,104 participants) also including other potential anti-inflammatory add-on interventions confirmed a significant, yet small, improvement in positive and negative symptom scores (7.1%) with statins relative to placebo [65]. In contrast, another meta-analysis (56 studies, 4,327 participants) found no significant benefit from an add-on statin [66]. Shen et al. [67] embarked on an ambitious meta-analysis not only to evaluate if statins improved negative or positive symptoms but also to see if different classes of statins have differential effects, if different types of antipsychotics combined with statins had a different effect, and finally, to measure the effect of the duration of treatment with statins. At week 12, a significant difference emerged in both positive and negative symptoms between the statin antipsychotic group vs. the placebo antipsychotic group. In terms of differences between statins, simvastatin manifested the strongest effect for both positive and negative symptoms, and it was the routine antipsychotics, rather than the new-generation antipsychotics, that showed improvement in both positive and negative symptoms [67]. The authors explained their finding in terms of both statins (simvastatin [68], atorvastatin, rosuvastatin, pravastatin, and lovastatin [69,70]), and antipsychotics (strongest with risperidone [and quetiapine] and weakest for haloperidol and clozapine) being P-gp substrates of P-glycoprotein 1 (P-gp), also called ATP-binding cassette sub-family B member 1 (ABCB1). Antipsychotic agents interact with statins through competition for P-gp transport. Being co-substrates, the lower affinity antipsychotics and statins will result in reciprocal greater access to the CNS; the results indeed supported a considerable component of the effect of statins on negative symptoms to be the result of interactions between statins and the type of the antipsychotic.

What could explain the beneficial effect of statins in schizophrenia reported by the majority of the meta-analyses published to date, in particular in regard to domains that are so resilient to neuroleptic treatment, such as negative symptoms and cognitive deficits? Indeed, negative symptoms and cognitive deficits in schizophrenia are the two symptomatic domains least responsive to treatment and most contributory to functional deficits in individuals with the illness. Immune activation has been increasingly identified in individuals with schizophrenia, and, in particular, proinflammatory signals are associated with the severity of cognitive dysfunction and negative symptoms [71,72] with likely disruptive effects on synaptic signaling, neurogenesis, neuroprotection, axonal/neurite growth, and thus connectivity [73]. In addition, oxidative stress, in part a consequence of a proinflammatory and excitotoxic milieu, disrupts parvalbumin interneurons. The disruption of these interneurons localized in the cortex and hippocampus, known to have an increased vulnerability to oxidative stress, may centrally contribute to the production of cognitive dysfunction and negative symptoms [74]. In addition, executive dysfunction in schizophrenia is also, in part, a consequence of increased oxidative stress, as illustrated peripherally by several molecular systems, such as glutathione/GSH and, centrally, via reduced neurotrophic factors, such as brain-derived neurotrophic factor (BDNF) [75]. All these targets, the oxidative stress, neuroinflammation, neuroprotective and neurotrophic deficits, and molecular inflammation cascades are engaged and modulated by statins [76,77].

1.3.6 Statins in bipolar disorder

Similarly, individuals with bipolar disorder also have clinical and preclinical evidence for immune dysregulation, with the elevation of proinflammatory cytokines relative to psychiatric and normal controls, including IL-6, tumor necrosis factor (TNF)-α, IL-1β, soluble receptor of TNF-type 1 (STNFR1), and soluble interleukin-2 receptor (sIL-2R) [78,79,80,81,82,83,84]. Isolated reports have been confirmed in a recent systematic review/meta-analysis that documented a “trait-like” elevation of proinflammatory signals during both mania and depression episodes, reverting to normal values after return to euthymia [85]. Of functional importance, the markers of immune activation are positively associated with cognitive status, as well as neuroanatomical changes [86,87,88,89,90]. Yet not all studies have found evidence of neuroinflammation in BD [91]. In contrast with the classical view of bipolar disorder being in principle an episodic condition with full restoration to normality, there is evidence that residual mood and cognitive symptoms, functional impairment, decreased quality of life, and psychosocial disability exist even when the condition is appropriately treated [92,93]. Moreover, there is evidence for bipolar disorder being a progressive condition, often in the context of nonadherence and inappropriate treatment resulting in highly recurrent mood episodes, incomplete interepisodic remission, progressive cognitive impairment, and functional decline [94,95,96], with specific neurobiological underpinnings characterizing different stages and longitudinal progression of bipolar disorder (“neuroprogression”) [97,98,99,100,101,102]. Of relevance for possible treatment targeting by statins, neuroprogression has been linked to enhanced oxidative stress, breakdown of the neurotrophic support, mitochondrial dysfunction, and decreased cellular resilience, in part as a result of persistent and cascading immune dysfunction [99,100,103,104], leading to the loss of neuroprotection, excitotoxicity, apoptosis, and loss of cortical volume. Yet not all studies agree with the neuroprogression hypothesis in bipolar disorder, in particular with the accelerated cognitive decline with aging [100,105].

1.4 The tryptophan degradation and the kynurenine pathway

Immune activation and stress lead to activation of enzymatic systems such as indoleamine 2,3-dioxygenase (IDO) or tryptophan 2,3-dioxygenase (TDO), resulting in increased production of kynurenines and decreased tryptophan [106]. Mitigating potential pathogenic effects of infection, the decrease of tryptophan affects multiplication of microbes, preventing unchecked invasion of the organism, and kynurenine production is immune regulatory, preventing unremitting inflammation. Kynurenine can cross the blood–brain barrier (BBB) freely and is degraded to molecules produced locally without the capability to freely cross the BBB. These have excitotoxic effects (e.g., quinolinic acid [QA]) or inhibitory effects (kynurenic acid [KA]) on brain structure or function. Suicidal behavior is associated with elevations in kynurenine [107] and QA [108,109], while schizophrenia [110,111] and BD with history of psychotic episodes [112] are associated with with elevations of KA. More recently, positive associations between cognitive deficits in schizophrenia and QA in schizophrenia have been reported, suggesting a state of excitotoxic necrosis as the basis of these symptoms, highly relevant for functioning, rehabilitation, and prevention of suicidal behavior in schizophrenia [113]. Dysregulation of the kynurenine pathway has also been implicated in BD and its progression [114], as well as state severity of depression in patients with bipolar disorder [115].

1.5 Statins: Anti-inflammatory and immune regulatory effects

Statins generally decrease, in a concentration-dependent manner, the production of neopterin and degradation of tryptophan in ex vivo models, such as peripheral blood mononuclear cells (PBMCs) stimulated by IFN-gamma, concanavalin A (ConA), and phytohemagglutinin (PHA) [116]. In patients with suspected stable angina pectoris who are taking statin therapy after angiography, increased neopterin level is associated with the increased risk of acute myocardial infarction (AMI) [117]. Consistent with these findings, in patients with acute coronary syndrome (ACS), higher neopterin levels predict the increased long-term risk of death and nonfatal coronary events. In these patients, high-dose statin treatment reduces neopterin levels, while decreasing coronary mortality and nonfatal coronary events [118]. Statins inhibit the cellular proliferation of PBMCs induced by different antigens, such as T–B polyclonal stimuli and Staphylococcus aureus enterotoxin A (SEA) [119].

However, not all studies have concordant results. For instance, in one clinical longitudinal study, statins led to decreased C-reactive protein (CRP) levels, but had no effect on neopterin levels and autoantibody titers (such as antinuclear antibodies) [120]. Furthermore, a double-blind placebo-controlled randomized trial of statin administration found no significant change in inflammation biomarkers (neopterin, CRP) [121].

Statins also manifest immune-modulatory effects by activating regulatory T cells (Tregs). For example, in a murine model of tumor growth, statins activate Treg and increase the production of the immune regulatory markers IL-10 and TGF-β1 [122]. Statins reduce the number and increase the suppressive function of Treg cells in animal experimental models of chronic immune activation [123] and in humans with or without immune-mediated conditions [124]. The production of Tregs is linked with the production of reactive oxygen species (ROS) geared at a minimum toward eliminating pathogens, at most, to regulate the balance between proinflammatory and regulatory arms of the immune response [125]. This has a narrow regulatory window as specifically unopposed ROS production can suppress regulatory T cell production in favor of proinflammatory reactions, or alternatively, very little ROS production may also impair the differentiation, stability, and suppressive function of Tregs [125].

Statins not only reduce the production of kynurenine but also actively limit the effects of kynurenine’s main excitotoxic metabolite, QA. For example, in a model of QA-induced neurotoxicity in rats, statins significantly decrease the excitotoxic effect of QA, levels of markers of oxidative stress, and proinflammatory cytokines (such as TNF-α) as well as striatal lesion volume [126]. In another study, statins appear to have a neuroprotective effect in excitotoxic rodent seizure models. Specifically, atorvastatin significantly reduced QA-induced clonic and/or tonic seizures and prevented cell death induced by QA in the hippocampus [127]. Atorvastatin also counteracts the decrease in glutamate uptake triggered by QA and prevents the QA-induced decrease in protein kinase B (PKB, or Akt) phosphorylation [128].

1.6 Lipophilic vs. hydrophilic statins

Statins are characterized by different degrees of lipophilicity and divided into lipophilic and hydrophilic categories. While both groups have a similar efficacy in reducing cardiovascular and general mortality and overall side effects [129], the lipophilic statins cross more readily the BBB [130] and thus raise the hope that they could have a more pronounced local anti-inflammatory, antioxidant, neuroprotective, and endothelial-stabilizing effect within the CNS, and lead to improvement in conditions with clear primary brain localization of pathological processes. On the other hand, their potential toxic effects on cellular lipid components of membranes in affecting transmembrane receptors and channels, and other deleterious molecular effects within the brain could offset, at least partially, the beneficial CNS effects of statins [76,77].

1.7 Rationale and hypotheses

The increasing understanding of immune dysregulation across diagnostic categories of mental illness, including MD, BD, schizophrenia, and dementias (of Alzheimer’s type, vascular type), has been the number one rationale to consider using add-on statins, especially in individuals who already have medical indications. Indeed, several meta-analyses, increasingly including randomized clinical trials (RCT), support the clinically beneficial effects of add-on statins in depression and schizophrenia, although meta-analytic and RCT exceptions exist. Similarly, statins appear to have been beneficial in cognitive disorders by slowing cognitive decline [131], reducing the risk of dementia [132], improving Mini-Mental scores, and slowing deterioration on neuropsychiatric inventory deficit scores [133].

A large population-based study on Danish nationals with MD treated with selective serotonin reuptake inhibitors (SSRIs) found a reduced hazard of psychiatric hospitalizations with concurrent statin use compared to a no statin treatment group (hazard ratio, 0.75; 0.64–0.75) [134]. To our knowledge, there is no equivalent study on hospital contacts in schizophrenia and BD. We now aimed to fill this gap. We went one step further: Because lipophilic statins and hydrophilic statins differ in terms of their ability to cross the BBB (specifically lipophilic statins being able to cross more readily the BBB, thus having effects also on the CNS, and not only peripherally, as the hydrophilic statins), we engaged the aim of comparing the two statin categories on their ability to prevent psychiatric hospitalizations and ED visits when added on to antipsychotic treatment (in schizophrenia and bipolar individuals) and mood stabilizer treatment (in bipolar individuals). In doing so, we intended to minimize confounding by indication and to take a first step in the direction of personalizing the choice of statins for individuals with mental health problems. We used VA administrative data on ER visits and psychiatric hospitalizations as well as VA pharmacy data. We hypothesized that add-on statins will be protective relative to no statin control and that differences between lipophilic and hydrophilic statins will emerge (two-tailed hypothesis). Psychiatric hospitalization and ED visits were pair-wise compared among the three statin prescription groups (lipophilic, hydrophilic, and none) separately in antipsychotic-treated individuals with schizophrenia, as well as antipsychotic- or mood stabilizer-treated individuals with BD, using robust Poisson regressions.

2 Methods

2.1 Overall design

Overall, this is a hypothesis-testing observational study using VA health care service utilization data from October 1, 2010 to September 30, 2015, including demographic, diagnostic, hospitalization, and ED visits, and all outpatient prescription medications dispensed from VA pharmacies, as reported in a recent publication using a similar methodology with the same dataset [135].

2.2 Data sources

This study used data on health services maintained at the U.S. Department of Veterans Affairs’ (VA) Corporate Data Warehouse (CDW). The study period was between October 1, 2010 and September 30, 2015. All healthcare inpatient and outpatient workloads provided to Veterans in VA hospitals and outpatient clinics across the US were included. Hospitalizations that occurred in non-VA hospitals were included via the VA fee base files.

  1. Ethical approval: This study was approved by the Institutional Review Board of the University of Maryland School of Medicine. The conducted research is not related to either human or animal use.

  2. Informed consent: Institutional Review Board of the University of Maryland School of Medicine approved a waiver of informed consent because we used only extant administrative data.

2.3 Sample selection

We selected all VA health records, which had, during the study period, at least one outpatient or inpatient ICD-9-CM code for schizophrenia (295×) or BD (code disorder (ICD-9-CM code of 296.0–1, 296.4–8). If other serious mental illness codes (296.×, 297.×, 298.×) were present, we assigned the diagnosis that was present during the majority of encounters in the study period. A total of 683,129 participants were included in this study. Among them, 185,449 were individuals with schizophrenia treated with antipsychotics, 211,412 were individuals with BD treated with antipsychotics and 286,268 were patients with BD treated with mood stabilizers.

2.4 Medications

Incident treatment episodes were constructed from prescription records. Lipophilic statins included prescriptions for simvastatin, atorvastatin, pitavastatin, and lovastatin. The hydrophilic statins included rosuvastatin, pravastatin, and fluvastatin. A total of 69.69% of individuals in the entire population during the duration of the study had at least one statin prescription dispensed at a VA pharmacy, with most commonly dispensed lipophilic statins being simvastatin (in 33.16% of individuals) followed by atorvastatin (18.07%), hydrophilic statins pravastatin (9.49%), and rosuvastatin (7.76%). Lovastatin, pitavastatin, and fluvastatin were seldomly dispensed (combined less than 2%). A treatment episode was defined as a continuous time interval of medication possession from the specific date of the incident prescription until the first prescribing time gap between prescriptions of more than 15 days. Gaps of at least 16 days past the expected refill date were considered clinically significant and consequently were interpreted as a discontinuation of a prescribed medication. Imperfect adherence was defined as gaps of 2 weeks or less, was considered clinically irrelevant and was ignored.

2.5 Outcomes

To help identify the average effect of each medication, we examined only incident prescribing episodes, defined here as no prescriptions for the same medication in the 6 months before the designated episode start date. To ensure sufficient numbers of individuals prescribed a medication with an adequate exposure period were available for analysis, we retained only those medications that had at least 100 individuals with schizophrenia or BD with episodes lasting at least 3 months. To facilitate the identification of episodes lasting at least 3 months, we limited analyses to episodes with start dates between April 1, 2011, and March 31, 2015.

2.6 Comparisons

We examined the relative risk (RR) of psychiatric hospitalization and ED visit during incident prescription episodes comparing lipophilic to hydrophilic statins, and also each statin group to a “no statin” control group. In each of the three analyses by diagnosis-psychiatric medication, the control group (no statin – “none”) consisted of all other nonpsychiatric incident medication episodes – excluding those for hydrophilic or lipophilic statins – that lasted 3 or more months for at least 100 individuals.

We only included patients who received a prescription of primary psychotropic medication during the 6 months before the start of the prescription episode. Individuals with schizophrenia were excluded if they did not have an antipsychotic prescription in the 6 months before the start of any episode, and individuals with BD were excluded if they were not on a mood stabilizer or antipsychotic during this period. As such, we performed three separate analyses for each outcome – one for patients with schizophrenia treated with antipsychotics, one for BD patients treated with antipsychotics, and one for BD patients treated with mood stabilizers.

2.7 Statistical analyses

We analyzed the data with the Statistical Analysis System (SAS) Version 9.4, Cary, NC. Robust Poisson regression [136] was used to estimate the RR of psychiatric hospitalization and ED visits comparing incident episodes of lipophilic vs. hydrophilic statin use and each statin vs. the “other” control group episodes. Robust Poisson regression provides accurate standard error estimates when the outcome is binary by using robust (“sandwich”) standard errors. The robust standard errors also account for within-individual correlation among repeated prescription episodes. In those with schizophrenia and those with BD on antipsychotic medication, we adjusted for age, gender, race, ever married, prior psychiatric hospitalization or ED visits, posttraumatic stress disorder (y/n), alcohol use disorder (y/n), other substance use disorder (y/n), antipsychotic coverage, mood stabilizer (y/n), and antidepressant (y/n) in the prior 6 months. In the group of bipolar individuals on mood stabilizers, all the covariates were identical, with the exception of antipsychotic coverage being replaced with antipsychotic (y/n) and mood stabilizer (y/n) being replaced with mood stabilizer coverage. A parallel analysis was performed to estimate RR of ED visits in the 6 months after the prescription episode began.

3 Results

3.1 Descriptive results

The participants with schizophrenia with antipsychotic medication had the mean (SD) age of 58.67 (9.99) years. The majority of these participants were men (91.66%) and white (60.13%; Table 1). The participants with BD on antipsychotic medication had the mean age (SD) of 54.77 (11.29) years. The majority of these participants were men (82.35%) and white (80.18%; Table 2). Their demographic composition was very similar to that of the bipolar participants on a mood stabilizer (Table 3).

Table 1

Description of individuals with schizophrenia on antipsychotic medication

Schizophrenia with antipsychotic Whole Lipophilic Hydrophilic None
N = 185,449 SD or % N = 11,293 SD or % N = 4,759 SD or % N = 169,397 SD or %
Mean age SD 58.67 9.99 58.49 9.5 58.18 9.38 58.7 10.03
Male 169,985 91.66% 10,480 92.80% 4,388 92.20% 155,117 91.57%
Race
  White 111,513 60.13% 7,007 62.05% 2,893 60.79% 101,613 59.99%
  Non-white 65,446 35.29% 3,761 33.30% 1,642 34.50% 6,0043 35.45%
  Missing 8,490 4.58% 525 4.65% 224 4.71% 7,741 4.57%
Ever married 124,317 67.04% 7,514 66.54% 3,279 68.90% 11,3524 67.02%
With service percentage ≥50% 102,312 55.17% 6,149 54.45% 2,661 55.92% 93,502 55.20%
Fiscal year
  FY11 24,502 13.21% 997 8.83% 893 18.76% 22,612 13.35%
  FY12 49,032 26.44% 1,660 14.70% 2,250 47.28% 45,122 26.64%
  FY13 47,452 25.59% 3,903 34.56% 843 17.71% 42,706 25.21%
  FY14 43,940 23.69% 3,371 29.85% 547 11.49% 40,022 23.63%
  FY15 20,523 11.07% 1,362 12.06% 226 4.75% 18,935 11.18%
Psychiatric condition
  Major depression 45,121 24.33% 2,613 23.14% 1,081 22.71% 41,427 24.46%
  PTSD 33,771 18.21% 1,913 16.94% 838 17.61% 31,020 18.31%
  Alcohol use disorder 36,316 19.58% 1,792 15.87% 731 15.36% 33,793 19.95%
  Other substance use disorder 34,198 18.44% 1,671 14.80% 660 13.87% 31,867 18.81%
Psychiatric medication use
  Prescribed ATP 185,449 100% 11,293 100% 4,759 100% 169,397 100%
  Antipsychotics coverage ≥80% 104,434 56.31% 6,431 56.95% 2,857 60.03% 95,146 56.17%
  Prescribed clozapine 7,473 4.03% 411 3.64% 159 3.34% 6,903 4.08%
  Prescribed mood stabilizer medication 75,709 40.82% 4,204 37.23% 1,829 38.43% 69,676 41.13%
  Mood stabilizer medication coverage ≥80% 37,797 20.38% 2,155 19.08% 942 19.79% 34,700 20.48%
  Prescribed antidepressant 118,310 63.80% 7,094 62.82% 3,044 63.96% 108,172 63.86%
  Prescribed anti-anxiety medication 77,130 41.59% 4,309 38.16% 1,873 39.36% 70,948 41.88%
  Prescribed substance use disorder medication 8,957 4.83% 430 3.81% 175 3.68% 8,352 4.93%
Service use
  Hospitalized for somatic reason 34,769 18.75% 1,557 13.79% 590 12.40% 32,622 19.26%
  Emergency room use 65,965 35.57% 3,241 28.70% 1,263 26.54% 61,461 36.28%
  PRRC visits 15.41 2.38 14.59 2.26 16.5 2.59 15.43 2.38
  MHICM visits 13 4.22 12.2 3.78 12.45 3.72 13.07 4.26
  Other mental health outpatient visits 12.8 7.63 12.6 7.07 13.48 7.12 12.79 7.68
  Substance use visits 8.69 1.39 7.07 1.06 7.68 1.08 8.81 1.43
  Somatic outpatient visits 18.36 18.22 16.55 15.79 17.15 16.43 18.5 18.44
  Somatic outpatient visits during 3M post 11.57 11.56 10.06 9.74 9.45 9.56 11.7 11.74
Carlson comorbidity index 4,524 40.06% 1,839 38.64% 64,872 38.30%
  0 71,235 38.41% 4,007 35.48% 1,700 35.72% 57,702 34.06%
  1 63,409 34.19% 2,762 24.46% 1,220 25.64% 46,823 27.64%
  2+ 50,805 27.40% 9.5 58.49 9.38 58.18 10.03 58.7

FY: Fiscal year in which incident medication episode began; PTSD: posttraumatic stress disorder; ATP: prescribed antipsychotic; PRRC: count of psychosocial rehabilitation and recovery center visits; MHICM: count of mental health intensive case management visits.

Table 2

Description of individuals with BD on antipsychotic medication

Bipolar with antipsychotic Whole Lipophilic Hydrophilic None
N = 211,412 SD or % N = 13,292 SD or % N = 5,326 SD or % N = 192,794 SD or %
Mean age SD 54.77 11.29 55.93 10.37 56.11 10.12 54.65 11.37
Male 174106 82.35% 11,424 85.95% 4,519 84.85% 158,163 82.04%
Race
  White 169,511 80.18% 10,919 82.15% 4,397 82.56% 154,195 79.98%
  Non-white 34,040 16.1% 1,843 13.87% 737 13.84% 31,460 16.32%
  Missing 7,861 3.72% 530 3.99% 192 3.60% 7,139 3.70%
Ever married 178,906 84.62% 11,373 85.56% 4,644 87.19% 162,889 84.49%
With service percentage ≥50% 93,123 44.05% 5,654 42.54% 2,226 41.79% 85,243 44.21%
Fiscal year
  FY11 25,504 12.06% 1,151 8.66% 1,041 19.55% 23,312 12.09%
  FY12 53,920 25.5% 1,864 14.02% 2,374 44.57% 49,682 25.77%
  FY13 54,168 25.62% 4,729 35.58% 1,018 19.11% 48,421 25.12%
  FY14 52,605 24.88% 3,931 29.57% 637 11.96% 48,037 24.92%
  FY15 25,215 11.93% 1,617 12.17% 256 4.81% 23,342 12.11%
Psychiatric condition
  Major depression 81,864 38.72% 4,732 35.60% 1,846 34.66% 75,286 39.05%
  PTSD 79,552 37.63% 4,483 33.73% 1,827 34.30% 73,242 37.99%
  Alcohol use disorder 56,951 26.94% 3,016 22.69% 1,118 20.99% 52,817 27.40%
  Other substance use disorder 50,489 23.88% 2,530 19.03% 980 18.40% 46,979 24.37%
Psychiatric medication use
  Prescribed ATP 211,412 100% 13,292 100% 5,326 100% 192,794 100%
  Antipsychotics coverage ≥80% 90,831 42.96% 6,001 45.15% 2,491 46.77% 82,339 42.71%
  Prescribed clozapine 361 0.17% 16 0.12% 8 0.15% 337 0.17%
  Prescribed mood stabilizer medication 137,213 64.9% 8,426 63.39% 3,435 64.49% 125,352 65.02%
  Mood stabilizer medication coverage ≥80% 65,707 31.08% 4,239 31.89% 1,725 32.39% 59,743 30.99%
  Prescribed antidepressant 159,677 75.53% 9,834 73.98% 3,970 74.54% 145,873 75.66%
  Prescribed anti-anxiety medication 111,319 52.66% 6,459 48.59% 2,718 51.03% 102,142 52.98%
  Prescribed substance use disorder medication 22,158 10.48% 1,129 8.49% 440 8.26% 20,589 10.68%
Service use
  Hospitalized for somatic reason 36,434 17.23% 1,748 13.15% 628 11.79% 34,058 17.67%
  Emergency room use 76,432 36.15% 3,905 29.38% 1474 27.68% 71,053 36.85%
  PRRC visits 8.93 0.92 8.42 0.88 9.1 0.94 8.96 0.92
  MHICM visits 6.36 0.96 5.82 0.83 5.51 0.8 6.42 0.97
  Other mental health outpatient visits 14.37 8.76 13.18 7.7 12.18 7.23 14.5 8.88
  Substance use visits 11.11 2.37 10 1.89 9.09 1.63 11.23 2.43
  Somatic outpatient visits 18 18.96 16.47 16.27 16.33 16.98 18.12 19.2
  Somatic outpatient visits during 3M post 11.88 12.15 10.29 9.9 9.91 9.89 12.01 12.37
Carlson comorbidity index
  0 96,283 45.54% 6,139 46.19% 2,337 43.88% 87,807 45.54%
  1 67,107 31.74% 4,316 32.47% 1,815 34.08% 60,976 31.63%
  2+ 48,022 22.71% 2,837 21.34% 1,174 22.04% 44,011 22.83%

FY: Fiscal year in which incident medication episode began; PTSD: posttraumatic stress disorder; ATP: prescribed antipsychotic; PRRC: count of psychosocial rehabilitation and recovery center visits; MHICM: count of mental health intensive case management visits.

Table 3

Description of individuals with BD on mood-stabilizer medication

Bipolar with mood stabilizer Whole Lipophilic Hydrophilic Other
N = 286,268 SD or % N = 18,267 SD or % N = 7,307 SD or % N = 260,694 SD or %
Mean age SD 55.41 11.34 56.8 10.3 56.87 10.13 55.28 11.43
Male 238,625 83.36% 15,976 87.46% 6,302 86.25% 216,347 82.99%
Race
  White 233,821 81.68% 15,221 83.33% 6,104 83.54% 21,2496 81.51%
  Non-white 41,238 14.41% 2308 12.63% 898 12.29% 38,032 14.59%
  Missing 11,209 3.92% 738 4.04% 305 4.17% 10,166 3.9%
Ever married 246,998 86.28% 15,971 87.43% 6502 88.98% 224,525 86.13%
With service percentage ≥50% 126,007 44.02% 7867 43.07% 2,990 40.92% 115,150 44.17%
Fiscal year
  FY11 32,946 11.51% 1,454 7.96% 1,418 19.41% 30,074 11.54%
  FY12 71,876 25.11% 2,478 13.57% 3,346 45.79% 66,052 25.34%
  FY13 73,489 25.67% 6,626 36.27% 1,269 17.37% 65,594 25.16%
  FY14 73,066 25.52% 5,457 29.87% 896 12.26% 66,713 25.59%
  FY15 34,891 12.19% 2,252 12.33% 378 5.17% 32,261 12.38%
Psychiatric condition
  Major depression 109,158 38.13% 6,404 35.06% 2,503 34.25% 10,0251 38.46%
  PTSD 100,897 35.25% 5,878 32.18% 2,314 31.67% 92,705 35.56%
  Alcohol use disorder 69,117 24.14% 3,678 20.13% 1,366 18.69% 64,073 24.58%
  Other substance use disorder 59,663 20.84% 2,964 16.23% 1,072 14.67% 55,627 21.34%
Psychiatric medication use
  Prescribed ATP 137,213 47.93% 8,426 46.13% 3,435 47.01% 125,352 48.08%
  Antipsychotics coverage ≥80% 60,215 21.03% 3,909 21.4% 1,600 21.9% 54,706 20.98%
  Prescribed clozapine 277 0.1% 13 0.07% 4 0.05% 260 0.1%
  Prescribed mood stabilizer medication 286,268 100% 18,267 100% 7,307 100% 260,694 100%
  Mood stabilizer medication coverage ≥80% 129,612 45.28% 8,582 46.98% 3,489 47.75% 117,541 45.09%
  Prescribed antidepressant 211,314 73.82% 13,191 72.21% 5,299 72.52% 192,824 73.97%
  Prescribed anti-anxiety medication 142,628 49.82% 8,294 45.4% 3,471 47.5% 130,863 50.2%
  Prescribed substance use disorder medication 26,805 9.36% 1,309 7.17% 519 7.1% 24,977 9.58%
Service use
  Hospitalized for somatic reason 49,987 17.46% 2470 13.52% 907 12.41% 46,610 17.88%
  Emergency room use 101,884 35.59% 5441 29.79% 2050 28.06% 94,393 36.21%
  PRRC visits 7.7 0.71 7.45 0.68 7.27 0.61 7.73 0.71
  MHICM visits 5.17 0.64 4.61 0.54 4.58 0.55 5.22 0.65
  Other mental health outpatient visits 13.71 7.96 12.2 6.83 11.36 6.38 13.87 8.08
  Substance use visits 10.65 2.16 9.67 1.65 8.92 1.4 10.76 2.22
  Somatic outpatient visits 18.45 19.88 16.63 17.21 16.95 17.85 18.59 20.12
  Somatic outpatient visits during 3M post 12.2 12.64 10.61 10.52 10.42 10.51 12.33 12.85
Carlson comorbidity index
  0 125,230 43.75% 7,964 43.6% 3,035 41.54% 114,231 43.82%
  1 90,077 31.47% 5,947 32.56% 2,461 33.68% 81,669 31.33%
  2+ 70,961 24.79% 4,356 23.85% 1,811 24.78% 64,794 24.85%

FY: Fiscal year in which incident medication episode began; PTSD: posttraumatic stress disorder; ATP: prescribed antipsychotic; PRRC: count of Psychosocial Rehabilitation and Recovery Center visits; MHICM: count of Mental Health Intensive Case Management visits.

3.2 Hypothesis testing analysis

The RR of psychiatric hospitalization was higher in those prescribed lipophilic statins in comparison to those prescribed hydrophilic statins in all three diagnosis X treatment groups, in individuals with schizophrenia on antipsychotic medication (RR = 1.11; CI, 1.0007–1.23; p = 0.048), in individuals with BD on antipsychotic medication (RR = 1.22; CI, 1.09–1.36; p = 0.001), and in individuals with BD on mood stabilizers (RR = 1.18; CI, 1.06–1.32; p = 0.002; Table 4). The RR of psychiatric hospitalization was lower in those prescribed either statin (lipophilic vs. hydrophilic) than in the control “no statin” group (Table 4).

Table 4

Inpatient psychiatric hospitalization in individuals with schizophrenia and bipolar disorder; comparison between lipophilic, hydrophilic, and no statin groups

Label Relative risk Mean L’Beta estimate Standard error Alpha L’Beta Chi-square p
Confidence limit Confidence limit
Lipophilic vs. hydrophilic
  Schizophrenia with antipsychotic 1.11 1.0007 1.23 0.1 0.05 0.05 0.0007 0.21 3.89 0.048
  BD with antipsychotic 1.22 1.09 1.36 0.2 0.06 0.05 0.08 0.31 11.42 <0.001
  BD with mood stabilizer 1.18 1.06 1.32 0.17 0.05 0.05 0.06 0.27 9.37 0.002
Lipophilic vs. none
  Schizophrenia with antipsychotic 0.81 0.77 0.86 −0.21 0.03 0.05 −0.26 −0.16 59.84 <0.001
  BD with antipsychotic 0.85 0.80 0.89 −0.17 0.03 0.05 −0.22 −0.11 36.88 <0.001
  BD with mood stabilizer 0.83 0.79 0.88 −0.18 0.03 0.05 −0.23 −0.13 49.31 <0.001
Hydrophilic vs. none
  Schizophrenia with antipsychotic 0.73 0.67 0.80 −0.31 0.05 0.05 −0.40 −0.22 47.16 <0.001
  BD with antipsychotic 0.70 0.63 0.77 −0.36 0.05 0.05 −0.46 −0.26 50.07 <0.001
  BD with mood stabilizer 0.70 0.64 0.77 −0.35 0.05 0.05 −0.44 −0.26 53.89 <0.001

BD: bipolar disorder.

After adjustment, there were no statistical differences in the RR for ED visits between lipophilic and hydrophilic statins in all three diagnosis X treatment groups, in individuals with schizophrenia on antipsychotic medication (RR = 1.07; CI, 0.83–1.36; p = 0.61), in individuals with BD on antipsychotic medication (RR = 1.26; CI, 0.97–1.63; p = 0.08), and in individuals with BD on mood stabilizers (RR = 1.16; CI, 0.92–1.46; p = 0.2). The differences between each statin group and control “no statin” group were robust, with lower RR of ER visits in those on either statin group relative to controls (see Table 5).

Table 5

Psychiatric emergency department visit in individuals with schizophrenia and bipolar disorder; comparison between lipophilic, hydrophilic, and no statin groups

Label Relative risk Mean L’Beta estimate Standard error Alpha L’Beta Chi-square p
Confidence limit Confidence limit
Lipophilic vs. hydrophilic
  Schizophrenia with antipsychotic 1.07 0.83 1.36 0.06 0.13 0.05 −0.18 0.31 0.27 0.61
  BD with antipsychotic 1.26 0.97 1.63 0.23 0.13 0.05 −0.03 0.49 3.11 0.08
  BD with mood stabilizer 1.16 0.92 1.46 0.15 0.12 0.05 −0.08 0.38 1.63 0.2
Lipophilic vs. none
  Schizophrenia with antipsychotic 0.76 0.67 0.87 −0.27 0.07 0.05 −0.41 −0.14 16.44 <0.001
  BD with antipsychotic 0.83 0.74 0.94 −0.18 0.06 0.05 −0.31 −0.06 8.44 0.004
  BD with mood stabilizer 0.79 0.71 0.89 −0.23 0.06 0.05 −0.35 −0.12 16.09 <0.001
Hydrophilic vs. none
  Schizophrenia with antipsychotic 0.71 0.58 0.88 −0.34 0.11 0.05 −0.55 −0.13 10.03 0.002
  BD with antipsychotic 0.66 0.53 0.83 −0.41 0.12 0.05 −0.64 −0.19 12.93 <0.001
  BD with mood stabilizer 0.68 0.56 0.83 −0.38 0.1 0.05 −0.58 −0.18 14.09 <0.001

BD: bipolar disorder.

4 Discussion

4.1 Key results in context

The add-on of either lipophilic or hydrophilic statin prescription to US Veterans diagnosed with and treated for BD or schizophrenia was associated with a lower RR of psychiatric hospitalizations or ED visits as previously reported for patients with MD treated with SSRIs [134]. The add-on hydrophilic statins prescribed to individuals with BD and schizophrenia had a lower RR of psychiatric hospitalizations, but not of ED visits, than the lipophilic statin prescription in the same clinical groups. Although no similar comparisons between lipophilic and hydrophilic statins have been undertaken, to our knowledge, the results of a protective effect of statin use on hospitalization rates were consistent with one study nested in Danish registers showing that statin (simvastatin) treated patients with citalopram had fewer hospital contact than patients treated with SSRI alone [137]. The results are also consistent with a military study, revealing the increased risk of developing schizophrenia symptoms in nonpersistent statin users vs. persistent statin users [131]. It is important to keep in mind that the majority of studies of positive effects of statins on depression, schizophrenia, and on a delay of Alzheimer’s disease onset were based on lipophilic statins, and an elevated risk of suicidal ideation with statin (a common reason for psychiatric hospitalizations) has been also reported in lipophilic statin use only [138]. Yet direct comparisons between two statin categories have seldomly, if at all, been undertaken. Mild cognitive impairment [139,140] and sleep disturbances [141,142], both a consequence as well as a possible contributor to poor therapeutic control, occurred more commonly with lipophilic rather than hydrophilic statin administration, suggesting that brain penetrance may engage mechanisms that could offset, in part, anti-inflammatory, antioxidant, and endothelial positive effects of statins, perhaps via lowering cholesterol in the neuronal membranes and impairing channel and receptor function and/or mitochondrial function. However, this has to be interpreted with skepticism, as recent meta-analyses have not found any significant cognitive impairment of statin use with mild cognitive deficits [143,144] or with sleep efficiency or duration [145].

4.2 Confounding by indication

In comparisons between statins and no statins, there is a likely confounding by indication based on comorbidity with metabolic and cardiovascular conditions that may affect the response to medication, alter the risk of self-harm, and alter the risk of psychiatric hospitalization and ED visits. Methods to weigh, balance, or adjust for potential sources of bias, e.g., propensity score-matched analyses as in the supplemental material presented in the study by Kohler et al. [134], are deemed to remain incomplete without including the specific indications for statin treatment, such as low-density lipoprotein and total cholesterol measurement. Thus, our current comparison between statins and no statins, as Kohler’s finding in MD, should be received with considerable skepticism. Yet the comparison of lipophilic and hydrophilic statin minimizes bias [16] and may lead to an important decision point in those individuals who have schizophrenia or BD and meet the criteria to initiate or restart the statin treatment.

4.3 Statin effects on cognition and cognitive disorders

Cognitive deficits, as well as negative symptoms, are strongly predictive of functioning and course in schizophrenia and bipolar disorder and, although to a limited degree, are modifiable with add-on statin treatment [76,77]. Theoretically, statins could be particularly promising for cognitive deficits in individuals with schizophrenia and bipolar disorder as they have been reported by some (but not all) studies on cognitive deficits in the context of aging (age-related cognitive decline) and dementia. For instance, in community-dwelling adults, slower cognitive decline [131] and fewer white matter abnormalities [146] have been associated with statin treatment.

Wong et al. (2013) performed a systematic review of 20 uncontrolled studies on 4 million participants and identified a mild beneficial effect in Alzheimer's dementia and all dementias. Similarly, Song et al. (2013), via a meta-analysis of 11 longitudinal cohort studies and 57,020 participants, with positive heterogeneity and no evidence of bias, identified an approximately 40% decreased risk of dementia with the use of statins [132]. At the same time, Swiger et al. found in a meta-analysis of 11 studies with 23,443 individuals [144] enrolled in RCTs and prospective cohort studies identified a 29% protective effect of statins at the long term (>1 year), while there were no immediate benefits at a short term (<1 year). Most recently, the meta-analysis of Xuan et al (2020) on exclusively RCTs (nine studies) and 1,489 participants, uncovered a statistical improvement in cognitive function by Mini-Mental score and a reduced progression of worsening based on the Neuropsychiatric Inventory Questionnaire, but with no differences in other measures [133].

In a recent large study, bipolar individuals using neurocognitive testing belonging to four cognitive domains, statin users and nonusers did not differ in regard to cognitive function [15]. The authors concluded that statins neither improve nor deteriorate cognitive functioning in bipolar patients [147]. They suggested that inherent cognitive deterioration secondary to bipolar disorder, i.e., “neuroprogression” [105,148], and aging per se [100] outweigh the beneficial effects of statin treatment.

Statins have been linked also with mild cognitive impairment [149,150,151], findings that stand in full opposition to those reporting a delayed decline in cognitive function in older adults [149,150,151], with several studies that found no significant association [143,144]. Of relevance and congruent with our current report, clinical trials of hydrophilic statins did not elicit any cognitive deficits [76], while lipophilic studies were associated with mild cognitive impairment [139,140].

4.4 Biological mechanisms potentially contributing to our key results

4.4.1 Immune modulatory effects

Statins increase the number and increase the suppressive function of Treg cells in animal experimental models of chronic immune activation [123], clinically both in the presence and in the absence of immune-mediated conditions [124]. In addition, an increasing number of randomized controlled studies and meta-analyses support substantial benefits of statins as add-on interventions in various mental health conditions. The benefits of statins in mental health have been attributed to several molecular, cellular, and system effects, including modulating inflammation and endothelial function and reducing oxidative stress [18]. In particular, for the diagnostic categories analyzed in this project, the immunoregulatory effects of statins specifically engage and modulate proinflammatory targets associated with cognitive dysfunction and negative symptoms [71,72], key determinants of functioning in schizophrenia. In addition, statins have been reported to modulate molecular and cellular signatures involved in the trait-like immune activation during mania and depression in BD [85] as well as the progressive immune dysfunction [99,100,103,104] linked with the cognitive and functional decline in “neuroprogressive” cases of BD [97,98,99,100,101,102]. Most importantly, in conditions of acute neuro-adversity known to be downstream mediated by systemic inflammation and oxidative stress, statins have an overall immunoregulatory effect. For instance, in a murine model of TBI, atorvastatin significantly increases the proportion of regulatory T cells (Tregs) in both the periphery (spleen) and the brain and simultaneously increases their main immunoregulatory effectors – anti-inflammatory cytokines such as IL-10 and TGF-β1 [152], with the reduction in histopathology and functional recovery.

4.4.2 Antimicrobial effects

Statins are also potent add-on antimicrobial agents by interfering with mechanisms that pathogens use to evade the immune response and preventing immune overactivation and unremitting activation, which might have an important role in preventing reactivation of latent infections, such as chronic toxoplasmosis, implicated in schizophrenia [153] or suicidal behavior in individuals with schizophrenia [51] or with recurrent mood disorders [49,154].

4.4.3 Potential mechanisms for lipophilic vs. hydrophilic divergence

What mechanisms could underlie the difference in outcome between the lipophilic and hydrophilic statins? First, cognitive dysfunction may be elevated in the group of statins with penetrance in the brain, potentially through affecting neurotransmitter receptors, ion channels (via changes in the cholesterol component of lipid membranes), or, as in Alzheimer’s Dementia, induction of axonal degeneration due to deprivation of cholesterol as shown in cultured neurons [155]. Furthermore, a much more intense lowering of brain cholesterol by the lipophilic statins – with no cholesterol intake possible from outside the CNS – may affect brain serotonin synthesis, thus impulsivity, aggression, anxiety, violent ideation, and thus increased risk for self-directed violence [156158], and, in response, ED visits and psychiatric hospitalizations.

In addition, another interactive effect is possible, i.e., local intense antioxidant effect by lipophilic statins within the CNS may adversely affect the TH1 immune pressure on intracellular pathogens such as CMV or Toxoplasma gondii, which may result in reactivation of the pathogens and loss of therapeutic control. Furthermore, the plunging of brain ROS levels could also affect the maturation and function of Tregs, with reduced mediation of immunomodulatory signals (such as IL-10) and overshooting of inflammatory reactions promoting, among other mechanisms, persistent microglia hyperreactivity. For instance, in cell cultures, TNF-α upregulation and microglia activation [159,160] and induction of the mitochondrial apoptotic pathways, time and dose-dependent, have been reported with lovastatin [161].

4.4.4 Panorgan endothelial-stabilizing effects of statins

Furthermore, the effects of statins on stabilizing endothelial function [19] could be, in conjunction with their peripheral anti-inflammatory effect, the most important mechanisms for symptomatic, functional, and behavioral effects of statins, and thus, the effect on brain and behavior would primarily take place via diffuse vascular mechanisms. This has been best documented for rosuvastatin, the most commonly prescribed hydrophilic statin in our sample, given its potency and vascular tropism, and devoid of the added toxicity of penetration of brain parenchyma with lipophilic statins, such as the toxic effects on brain mitochondrial pathways.

Several molecular underexplored mechanisms could underlie the effects of statins. As autophagy-related pathway impairment has been reported in schizophrenia [162], it is possible that statin-mediated neuroprotection is based, at least in part, on restored autophagic mechanisms as robustly reported for rosuvastatin (the most prescribed hydrophilic statin) in Parkinson’s disease [163].

4.4.5 Statin kinetic interactions with psychotropic medications

First, coupling between a specific psychotropic agent and a specific statin may lead to interactions at the level of the cytochrome system involved in their metabolism resulting in blood level changes on the psychotropic, or of the statin. For instance, fluvastatin (lipophilic) and rosuvastatin are metabolized via CYP 2C9 and all others (with the exception of pravastatin) via CYP 3A4 [164]. Pravastatin is eliminated renally with minimal metabolism at the CYP system [165]. For example, the mood stabilizer carbamazepine is a strong inducer of the CYP 3A4 and thus is expected decrease the blood level of most statins, bringing it below the high-dose requirement that appears clinically necessary for effectively augmenting psychotropic medications or protecting cognitive function. On the other hand, the SSRI fluvoxamine, used almost exclusively in obsessive compulsive disorder (OCD), a condition often comorbid with schizophrenia, is a potent inhibitor of CYP 3A4, and thus resulting in considerable increases in levels for the majority of statins (thus meeting the high- dose requirements established for positive psychiatric effects based on early clinical impression, or, alternatively, contributing to toxicity and statin discontinuation). This combination may put a patient at a major risk for myopathy, liver and kidney toxicity, situations that for many patients practically represent an early end of statin treatment effects based on early clinical impression. Other potential interactions between statins and antipsychotics are based on competition for P-glycoprotein 1 (a BBB transporter guarding brain molecular access) and, being both substrates, act additively or synergistically for achieving a higher concentration in the CNS, leading to increased efficacy or amplified side effects [76]. This interaction is likely statin and antipsychotic specific based on specific P-glycoprotein 1 affinity (e.g., high for risperidone and low for clozapine or haloperidol) and, with advanced knowledge, amenable to deliberate statin by psychotropic coupling. These effects and specific interactions should be taken into considerations in future studies using machine learning to weigh potential effect modifiers and confounders among statin groups, individual statins, and statin/psychotropic combinations to identify sources of heterogeneity in clinical benefits.

4.4.6 Strength

We utilized a systematic data mining approach and yet a focused hypothesis-driven stance. The lipophilic vs. hydrophilic comparison is based on a dichotomy, central vs. peripheral effects, and known capability to cross the BBB. This comparison minimizes confounding and reduces bias.

4.4.7 Limitations

The generalizability might be relatively limited. We analyzed prescriptions (i.e., picking up the prescription) and not adherence based on actually taking the medications. We have not taken into consideration the relative potency of statins, the duration of administration, degree of adherence, and dosage (e.g., by accounting for a “dose-equivalent” across specific statins). The few studies that considered these variables suggested advantages for long duration and high dosages [166,167].

Time-varying confounders, such as interactions with psychiatric medications, have not been analyzed, and time-invariant confounders such as genetic factors and lifestyle characteristics could have biased our study. Observational design and the use of health services encounter data rather than clinical data, not weighing the statin vs. no statins groups, and the lack of biomarker measurements represents other limitations of the study.

In future studies, it will be relevant to measure markers of inflammation such as proinflammatory and anti-inflammatory cytokines, CRP, chemokines, neopterin measures of oxidative stress, markers of endothelial function, micro-RNA involved in proinflammatory and anti-inflammatory responses, physiological measurements of endothelial function, glucocorticosteroid measurement to consider effects of stress, acute and chronic, especially on TDO and immune function, tryptophan, kynurenine and molecules of the kynurenine pathway, precursors of dopamine affected by inflammation (phenylalanine, tyrosine, and their ratio), liver function tests (to monitor and account for statin toxicity), and of course, lipid profiles, especially total cholesterol, LDL cholesterol, and triglycerides. For large studies nested in electronic medical records, or for long-term monitoring, perhaps the most accessible and relevant clinical parameters are routine hematological laboratory results implicated in inflammation, such as WBC, neutrophil count, neutrophil/lymphocyte ratio, thrombocyte/lymphocyte ratio. The neutrophil:lymphocyte ratio (NLR) has been reported to be elevated in acute relapse in schizophrenia [168] and bipolar disorder [169], in particular in functionally relevant cognitive dysfunction and functional deterioration, as well as in increased suicide risk in euthymic bipolar individuals [170]. In tight experimental conditions, pretreatment with statins has been shown to prevent elevated NLR [171] after experimental stroke in rodents.

Future studies could be classified into two broad categories – studies of patients who have both metabolic/cardiovascular indications and psychiatric indications and, probably at a later stage, studies on individuals who have only psychiatric indications, with incomplete responses to psychotropic medication. The outcome of the interventions could be psychiatric admissions (as done in this article), psychiatric instability (perhaps as a composite measure, including parameters related to stability–instability of mental illness, such as admissions, emergency room visits, need to increase medication dosages or replace medications, notable changes in the level of functioning [academic, occupational, activities of daily living, maintaining relationships], trouble with the law, loss of housing, remission, relapse, or recurrence of substance abuse, and nonadherence with psychiatric medications and follow-up, and with larger samples – suicide attempts, episodes of violence, or, with even larger samples – mandating multicenter collaboration – death by suicide). Either by design, or by analysis (adjustment, stratification, postrandomization weighing), the intervention and control groups (statin vs. no statin randomization, and lipophilic vs. hydrophilic statin) would have to take into account demographic factors (age and gender), metabolic/cardiovascular indications of statins, substance use, psychiatric diagnosis (schizophrenia or bipolar I), its severity and treatment, and history of immune-mediated conditions (autoimmune, allergic, severe or persistent infections, and TBI). In particular, baseline markers of immune activation could represent criteria of inclusion (i.e., in line with the idea that inflammation must be present to be valuable to modulate it) or stratification. Machine learning paradigms could be employed for both weighing factors that may contribute to the outcome, analyzing heterogeneity of effects (i.e., what combination of demographic, clinical, and pharmacological factors predict the strongest effect size, or in contrast little or no benefit, or side effects of statin treatment). In essence, it will be important to know not only if statins have benefits, but also which categories of statins, which dosages, and what durations manifest the greatest psychiatric benefits, and what are the broad characteristics of patients most likely to benefit from statin add-on treatment.

4.4.8 Implications and future plans

In sum, this study identified that while both subgroups of statins are associated with lower RR of psychiatric hospitalization and ED visits, hydrophilic statins were advantageous in reducing the risk of psychiatric hospitalizations compared to lipophilic studies. The difference between hydrophilic and lipophilic statins was relatively small, and yet, given the proportion of individuals who are taking statins, this small effect may result in public health implications given the large number of individuals struggling with mental health issues, the increased metabolic and cardiovascular morbidity, and mortality in patients with severe mental illness.

Given the high proportion of Veterans with the history of mental illness who are being treated with a statin, the augmentation of psychotropic treatment in schizophrenia and BD with an individualized statin may have broad positive consequences. Understanding not only if statins help therapeutic controls but also what are the demographic, clinical, and pharmacologic characteristics of subgroups of patients who would benefit the most, and by which specific statin regimen (considering the lipophilia, potency, dose, and individual pharmacokinetic properties) is necessary. These efforts may lead to improved therapeutic control by repurposing statins as an add-on intervention in individuals in mental health treatment.

5 Conclusion

As pharmacological agents that engage multiple molecular targets implicated in onset, severity, and poor therapeutic control in schizophrenia and BD, personalized statin augmentation may become a salient, efficient, and nonstigmatizing intervention for reducing ER visits and hospitalization, achieving and sustaining remission, and maximizing functional recovery.

Acknowledgements

We thank Hira Mohyuddin, A. Dagdag and T. Stubborn for general support, including comments on the final versions of the manuscript and help with proofing this article.

  1. Funding information: Dr Teodor T. Postolache receives funding from the Department of Veterans Affairs (VA) Rocky Mountain Mental Illness Research, Education and Clinical Center (MIRECC) for Suicide Prevention (Aurora, Colorado). He is the PI of a Clinical Science Research and Development (CSR&D) Merit Award (number 1 I01 CX001310-01), which supported in part his participation in this related object. Dr Julie A. Kreyenbuhl is the PI on R01MH113650 funded by the National Institute of Mental Health, supporting, in part, this project. The other authors state no funding involved. The views, opinions and findings contained in this article belong to the authors and do not necessarily represent the official positions of the National Institutes of Health or the Veterans Health Organization.

  2. Conflict of interest: Dr Michael Miller receives advisory panel payments from Amarin, 89bio and Pfizer. Dr Christopher A. Lowry serves on the Scientific Advisory Board of Immodulon Therapeutics, Ltd., is Cofounder and Chief Scientific Officer of Mycobacteria Therapeutics Corporation, serves as an unpaid scientific consultant to Aurum Switzerland AG, and is a member of the Faculty of the Integrative Psychiatry Institute. The other authors state no conflict of interest.

  3. Data availability statement: The data are not available for direct sharing considering that the data do not belong to the authors, but to the Veterans Health Administration, and there is no provision approved by Institutional Review Board (IRB). Interested individuals should contact the authors via email of possible collaborations.

References

[1] Kroll DS, Karno J, Mullen B, Shah SB, Pallin DJ, Gitlin DF. Clinical severity alone does not determine disposition decisions for patients in the emergency department with suicide risk. Psychosomatics. 2018 Jul–Aug;59(4):388–93.10.1016/j.psym.2017.12.001Search in Google Scholar PubMed

[2] Olfson M, Wall M, Wang S, Crystal S, Liu SM, Gerhard T, et al. Short-term suicide risk after psychiatric hospital discharge. JAMA Psychiatry. 2016 Nov;73(11):1119–26.10.1001/jamapsychiatry.2016.2035Search in Google Scholar PubMed PubMed Central

[3] Chung DT, Ryan CJ, Hadzi-Pavlovic D, Singh SP, Stanton C, Large MM. Suicide rates after discharge from psychiatric facilities: a systematic review and meta-analysis. JAMA Psychiatry. 2017 Jul;74(7):694–702.10.1001/jamapsychiatry.2017.1044Search in Google Scholar PubMed PubMed Central

[4] Simonet D. Cost reduction strategies for emergency services: insurance role, practice changes and patients accountability. Health Care Anal. 2009 Mar;17(1):1–19.10.1007/s10728-008-0081-0Search in Google Scholar PubMed

[5] Yoon J, Yano EM, Altman L, Cordasco KM, Stockdale SE, Chow A, et al. Reducing costs of acute care for ambulatory care-sensitive medical conditions: the central roles of comorbid mental illness. Med Care. 2012 Aug;50(8):705–13.10.1097/MLR.0b013e31824e3379Search in Google Scholar PubMed

[6] Watkins KE, Pincus HA, Paddock S, Smith B, Woodroffe A, Farmer C, et al. Care for veterans with mental and substance use disorders: good performance, but room to improve on many measures. Health Aff (Millwood). 2011 Nov;30(11):2194–203.10.1377/hlthaff.2011.0509Search in Google Scholar PubMed

[7] Wagner TH, Sinnott P, Siroka AM. Mental health and substance use disorder spending in the Department of Veterans Affairs, fiscal years 2000–2007. Psychiatr Serv. 2011 Apr;62(4):389–95.10.1176/ps.62.4.pss6204_0389Search in Google Scholar PubMed

[8] Geller JL, Fisher WH, McDermeit M, Brown JM. The effects of public managed care on patterns of intensive use of inpatient psychiatric services. Psychiatr Serv. 1998 Mar;49(3):327–32.10.1176/ps.49.3.327Search in Google Scholar PubMed

[9] Richard-Lepouriel H, Weber K, Baertschi M, DiGiorgio S, Sarasin F, Canuto A. Predictors of recurrent use of psychiatric emergency services. Psychiatr Serv. 2015 May;66(5):521–6.10.1176/appi.ps.201400097Search in Google Scholar PubMed

[10] Blonigen DM, Macia KS, Bi X, Suarez P, Manfredi L, Wagner TH. Factors associated with emergency department useamong veteran psychiatric patients. Psychiatr Q. 2017 Dec;88(4):721–32.10.1007/s11126-017-9490-2Search in Google Scholar PubMed

[11] Doran KM, Raven MC, Rosenheck RA. What drives frequent emergency department use in an integrated health system? National data from the Veterans Health Administration. Ann Emerg Med. 2013 Aug;62(2):151–9.10.1016/j.annemergmed.2013.02.016Search in Google Scholar PubMed

[12] Irmiter C, McCarthy JF, Barry KL, Soliman S, Blow FC. Reinstitutionalization following psychiatric discharge among VA patients with serious mental illness: a national longitudinal study. Psychiatr Q. 2007 Dec;78(4):279–86.10.1007/s11126-007-9046-ySearch in Google Scholar PubMed

[13] Noronha SF, Desai PN. Psychiatric emergency services in the veterans health administration: a review. N Dir Ment Health Serv. 1999;1999(82):75–84.10.1002/yd.23319998210Search in Google Scholar PubMed

[14] Tsai J, Rosenheck RA. Risk factors for ED use among homeless veterans. Am J Emerg Med. 2013 May;31(5):855–8.10.1016/j.ajem.2013.02.046Search in Google Scholar PubMed

[15] 2020 National Veteran Suicide Prevention Annual Report. Office of Mental Health and Suicide Prevention: U.S. Department of Veterans Affairs; 2020.Search in Google Scholar

[16] Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019 Jun;139(25):e1082–143.10.1161/CIR.0000000000000698Search in Google Scholar PubMed

[17] Sabeel S, Motaung B, Ozturk M, Mukasa S, Kengne AP, Blom D, et al. Protocol for systematic review and meta-analysis: impact of statins as immune-modulatory agents on inflammatory markers in adults with chronic diseases. BMJ Open. 2020 Aug;10(8):e039034.10.1136/bmjopen-2020-039034Search in Google Scholar PubMed PubMed Central

[18] Walker AJ, Kim Y, Borissiouk I, Rehder R, Dodd S, Morris G, et al. Statins: neurobiological underpinnings and mechanisms in mood disorders. Neurosci Biobehav Rev. 2021 Sep;128:693–708.10.1016/j.neubiorev.2021.07.012Search in Google Scholar PubMed

[19] Ii M, Losordo DW. Statins and the endothelium. Vasc Pharmacol. 2007 Jan;46(1):1–9.10.1016/j.vph.2006.06.012Search in Google Scholar PubMed

[20] Ponce J, de la Ossa NP, Hurtado O, Millan M, Arenillas JF, Dávalos A, et al. Simvastatin reduces the association of NMDA receptors to lipid rafts: a cholesterol-mediated effect in neuroprotection. Stroke. 2008 Apr;39(4):1269–75.10.1161/STROKEAHA.107.498923Search in Google Scholar PubMed

[21] Lu D, Qu C, Goussev A, Jiang H, Lu C, Schallert T, et al. Statins increase neurogenesis in the dentate gyrus, reduce delayed neuronal death in the hippocampal CA3 region, and improve spatial learning in rat after traumatic brain injury. J Neurotrauma. 2007 Jul;24(7):1132–46.10.1089/neu.2007.0288Search in Google Scholar PubMed PubMed Central

[22] Greenwood J, Mason JC. Statins and the vascular endothelial inflammatory response. Trends Immunol. 2007 Feb;28(2):88–98.10.1016/j.it.2006.12.003Search in Google Scholar PubMed PubMed Central

[23] Liao JK. Isoprenoids as mediators of the biological effects of statins. J Clin Invest. 2002 Aug;110(3):285–8.10.1172/JCI0216421Search in Google Scholar

[24] Diamantis E, Kyriakos G, Quiles-Sanchez LV, Farmaki P, Troupis T. The anti-inflammatory effects of statins on coronary artery disease: an updated review of the literature. Curr Cardiol Rev. 2017;13(3):209–16.10.2174/1573403X13666170426104611Search in Google Scholar PubMed PubMed Central

[25] Greenwood J, Steinman L, Zamvil SS. Statin therapy and autoimmune disease: from protein prenylation to immunomodulation. Nat Rev Immunol. 2006 May;6(5):358–70.10.1038/nri1839Search in Google Scholar PubMed PubMed Central

[26] Morris G, Fernandes BS, Puri BK, Walker AJ, Carvalho AF, Berk M. Leaky brain in neurological and psychiatric disorders: drivers and consequences. Aust N Z J Psychiatry. 2018 Oct;52(10):924–48.10.1177/0004867418796955Search in Google Scholar PubMed

[27] Wang S, Xie X, Lei T, Zhang K, Lai B, Zhang Z, et al. Statins attenuate activation of the NLRP3 inflammasome by oxidized LDL or TNFα in vascular endothelial cells through a PXR-dependent mechanism. Mol Pharmacol. 2017 Sep;92(3):256–64.10.1124/mol.116.108100Search in Google Scholar PubMed

[28] Ampuero J, Romero-Gomez M. Prevention of hepatocellular carcinoma by correction of metabolic abnormalities: role of statins and metformin. World J Hepatol. 2015 May;7(8):1105–11.10.4254/wjh.v7.i8.1105Search in Google Scholar PubMed PubMed Central

[29] Ma Y, Chen Z, Zou Y, Ge J. Atorvastatin represses the angiotensin 2-induced oxidative stress and inflammatory response in dendritic cells via the PI3K/Akt/Nrf 2 pathway. Oxid Med Cell Longev. 2014;2014:148798.10.1155/2014/148798Search in Google Scholar PubMed PubMed Central

[30] Balakumar P, Mahadevan N. Interplay between statins and PPARs in improving cardiovascular outcomes: a double-edged sword? Br J Pharmacol. 2012 Jan;165(2):373–9.10.1111/j.1476-5381.2011.01597.xSearch in Google Scholar PubMed PubMed Central

[31] Li H, Kuwajima T, Oakley D, Nikulina E, Hou J, Yang WS, et al. Protein prenylation constitutes an endogenous brake on axonal growth. Cell Rep. 2016 Jul;16(2):545–58.10.1016/j.celrep.2016.06.013Search in Google Scholar PubMed

[32] Schneider EB, Efron DT, MacKenzie EJ, Rivara FP, Nathens AB, Jurkovich GJ. Premorbid statin use is associated with improved survival and functional outcomes in older head-injured individuals. J Trauma. 2011 Oct;71(4):815–9.10.1097/TA.0b013e3182319de5Search in Google Scholar

[33] Wang JY, Yao TC, Tsai YT, Wu AC, Tsai HJ. Increased dose and duration of statin use is associated with decreased asthma-related emergency department visits and hospitalizations. J Allergy Clin Immunol Pract. 2018 Sep–Oct;6(5):1588–95.e1.10.1016/j.jaip.2017.12.017Search in Google Scholar

[34] Tse SM, Li L, Butler MG, Fung V, Kharbanda EO, Larkin EK, et al. Statin exposure is associated with decreased asthma-related emergency department visits and oral corticosteroid use. Am J Respir Crit Care Med. 2013 Nov;188(9):1076–82.10.1164/rccm.201306-1017OCSearch in Google Scholar

[35] Vollmer T, Key L, Durkalski V, Tyor W, Corboy J, Markovic-Plese S, et al. Oral simvastatin treatment in relapsing-remitting multiple sclerosis. Lancet. 2004 May;363(9421):1607–8.10.1016/S0140-6736(04)16205-3Search in Google Scholar

[36] Réus GZ, Fries GR, Stertz L, Badawy M, Passos IC, Barichello T, et al. The role of inflammation and microglial activation in the pathophysiology of psychiatric disorders. Neuroscience. 2015 Aug;300:141–54.10.1016/j.neuroscience.2015.05.018Search in Google Scholar PubMed

[37] Berk M, Copolov D, Dean O, Lu K, Jeavons S, Schapkaitz I, et al. N-acetyl cysteine as a glutathione precursor for schizophrenia – a double-blind, randomized, placebo-controlled trial. Biol Psychiatry. 2008 Sep;64(5):361–8.10.1016/j.biopsych.2008.03.004Search in Google Scholar PubMed

[38] Chang SH, Chiang SY, Chiu CC, Tsai CC, Tsai HH, Huang CY, et al. Expression of anti-cardiolipin antibodies and inflammatory associated factors in patients with schizophrenia. Psychiatry Res. 2011 May;187(3):341–6.10.1016/j.psychres.2010.04.049Search in Google Scholar PubMed

[39] Song XQ, Lv LX, Li WQ, Hao YH, Zhao JP. The interaction of nuclear factor-kappa B and cytokines is associated with schizophrenia. Biol Psychiatry. 2009 Mar;65(6):481–8.10.1016/j.biopsych.2008.10.018Search in Google Scholar PubMed

[40] Misiak B, Bartoli F, Carrà G, Stańczykiewicz B, Gładka A, Frydecka D, et al. Immune-inflammatory markers and psychosis risk: a systematic review and meta-analysis. Psychoneuroendocrinology. 2021 May;127:105200.10.1016/j.psyneuen.2021.105200Search in Google Scholar PubMed

[41] Barichello T, Giridharan VV, Bhatti G, Sayana P, Doifode T, Macedo D, et al. Inflammation as a Mechanism of Bipolar Disorder Neuroprogression. Curr Top Behav Neurosci. 2020;48:215–37. Erratum in: Curr Top Behav Neurosci. 2020;48:325.10.1007/7854_2020_173Search in Google Scholar PubMed

[42] Keaton SA, Madaj ZB, Heilman P, Smart L, Grit J, Gibbons R, et al. An inflammatory profile linked to increased suicide risk. J Affect Disord. 2019 Mar;247:57–65.10.1016/j.jad.2018.12.100Search in Google Scholar PubMed PubMed Central

[43] Brundin L, Erhardt S, Bryleva EY, Achtyes ED, Postolache TT. The role of inflammation in suicidal behaviour. Acta Psychiatr Scand. 2015 Sep;132(3):192–203.10.1111/acps.12458Search in Google Scholar PubMed PubMed Central

[44] Tonelli LH, Stiller J, Rujescu D, Giegling I, Schneider B, Maurer K, et al. Elevated cytokine expression in the orbitofrontal cortex of victims of suicide. Acta Psychiatr Scand. 2008 Mar;117(3):198–206.10.1111/j.1600-0447.2007.01128.xSearch in Google Scholar PubMed PubMed Central

[45] Vasupanrajit A, Jirakran K, Tunvirachaisakul C, Maes M. Suicide attempts are associated with activated immune-inflammatory, nitro-oxidative, and neurotoxic pathways: a systematic review and meta-analysis. J Affect Disord. 2021 Aug;295:80–92.10.1016/j.jad.2021.08.015Search in Google Scholar PubMed

[46] Benros ME, Mortensen PB. Role of infection, autoimmunity, atopic disorders, and the immune system in schizophrenia: evidence from epidemiological and genetic studies. Curr Top Behav Neurosci. 2020;44:141–59.10.1007/7854_2019_93Search in Google Scholar PubMed

[47] Postolache TT, Wadhawan A, Rujescu D, Hoisington AJ, Dagdag A, Baca-Garcia E, et al. Toxoplasma gondii, suicidal behavior, and intermediate phenotypes for suicidal behavior. Front Psychiatry. 2021 Jun;12:665682.10.3389/fpsyt.2021.665682Search in Google Scholar PubMed PubMed Central

[48] Pedersen MG, Mortensen PB, Norgaard-Pedersen B, Postolache TT. Toxoplasma gondii infection and self-directed violence in mothers. Arch Gen Psychiatry. 2012 Nov;69(11):1123–30.10.1001/archgenpsychiatry.2012.668Search in Google Scholar PubMed

[49] Zhang Y, Träskman-Bendz L, Janelidze S, Langenberg P, Saleh A, Constantine N, et al. Toxoplasma gondii immunoglobulin G antibodies and nonfatal suicidal self-directed violence. J Clin Psychiatry. 2012 Aug;73(8):1069–76.10.4088/JCP.11m07532Search in Google Scholar PubMed

[50] Ling VJ, Lester D, Mortensen PB, Langenberg PW, Postolache TT. Toxoplasma gondii seropositivity and suicide rates in women. J Nerv Ment Dis. 2011 Jul;199(7):440–4.10.1097/NMD.0b013e318221416eSearch in Google Scholar PubMed PubMed Central

[51] Okusaga O, Langenberg P, Sleemi A, Vaswani D, Giegling I, Hartmann AM, et al. Toxoplasma gondii antibody titers and history of suicide attempts in patients with schizophrenia. Schizophr Res. 2011 Dec;133(1–3):150–5.10.1016/j.schres.2011.08.006Search in Google Scholar PubMed

[52] Gjervig Hansen H, Köhler-Forsberg O, Petersen L, Nordentoft M, Postolache TT, Erlangsen A, et al. Infections, anti-infective agents, and risk of deliberate self-harm and suicide in a young cohort: a nationwide study. Biol Psychiatry. 2019 May;85(9):744–51.10.1016/j.biopsych.2018.11.008Search in Google Scholar PubMed

[53] Lund-Sørensen H, Benros ME, Madsen T, Sørensen HJ, Eaton WW, Postolache TT, et al. A nationwide cohort study of the association between hospitalization with infection and risk of death by suicide. JAMA Psychiatry. 2016 Sep;73(9):912–9.10.1001/jamapsychiatry.2016.1594Search in Google Scholar PubMed

[54] Amritwar AU, Lowry CA, Brenner LA, Hoisington AJ, Hamilton R, Stiller JW, et al. Mental health in allergic rhinitis: depression and suicidal behavior. Curr Treat Opt Allergy. 2017 Mar;4(1):71–97.10.1007/s40521-017-0110-zSearch in Google Scholar PubMed PubMed Central

[55] Woo JM, Gibbons RD, Qin P, Komarow H, Kim JB, Rogers CA, et al. Suicide and prescription rates of intranasal corticosteroids and nonsedating antihistamines for allergic rhinitis: an ecological study. J Clin Psychiatry. 2011 Oct;72(10):1423–8.10.4088/JCP.10m06765Search in Google Scholar PubMed

[56] Postolache TT, Stiller JW, Herrell R, Goldstein MA, Shreeram SS, Zebrak R, et al. Tree pollen peaks are associated with increased nonviolent suicide in women. Mol Psychiatry. 2005 Mar;10(3):232–5.10.1038/sj.mp.4001620Search in Google Scholar PubMed PubMed Central

[57] Qin P, Waltoft BL, Mortensen PB, Postolache TT. Suicide risk in relation to air pollen counts: a study based on data from Danish registers. BMJ Open. 2013 May;3(5):e002462.10.1136/bmjopen-2012-002462Search in Google Scholar PubMed PubMed Central

[58] Parihar SP, Guler R, Brombacher F. Statins: a viable candidate for host-directed therapy against infectious diseases. Nat Rev Immunol. 2019 Feb;19(2):104–17.10.1038/s41577-018-0094-3Search in Google Scholar PubMed

[59] Salagre E, Fernandes BS, Dodd S, Brownstein DJ, Berk M. Statins for the treatment of depression: a meta-analysis of randomized, double-blind, placebo-controlled trials. J Affect Disord. 2016 Aug;200:235–42.10.1016/j.jad.2016.04.047Search in Google Scholar PubMed

[60] Köhler-Forsberg O, Lydholm CN, Hjorthøj C, Nordentoft M, Mors O, Benros ME. Efficacy of anti-inflammatory treatment on major depressive disorder or depressive symptoms: meta-analysis of clinical trials. Acta Psychiatr Scand. 2019 May;139(5):404–19.10.1111/acps.13016Search in Google Scholar PubMed

[61] Bai S, Guo W, Feng Y, Deng H, Li G, Nie H, et al. Efficacy and safety of anti-inflammatory agents for the treatment of major depressive disorder: a systematic review and meta-analysis of randomised controlled trials. J Neurol Neurosurg Psychiatry. 2020 Jan;91(1):21–32.10.1136/jnnp-2019-320912Search in Google Scholar PubMed

[62] De Giorgi R, De Crescenzo F, Rizzo Pesci N, Martens M, Howard W, Cowen PJ, et al. Statins for major depressive disorder: a systematic review and meta-analysis of randomized controlled trials. PLoS One. 2021 Mar;16(3):e0249409.10.1371/journal.pone.0249409Search in Google Scholar PubMed PubMed Central

[63] Abbasi SH, Mohammadinejad P, Shahmansouri N, Salehiomran A, Beglar AA, Zeinoddini A, et al. Simvastatin versus atorvastatin for improving mild to moderate depression in post-coronary artery bypass graft patients: A double-blind, placebo-controlled, randomized trial. J Affect Disord. 2015 Sep;183:149–55.10.1016/j.jad.2015.04.049Search in Google Scholar PubMed

[64] Nomura I, Kishi T, Ikuta T, Iwata N. Statin add-on therapy in the antipsychotic treatment of schizophrenia: a meta-analysis. Psychiatry Res. 2018 Feb;260:41–7.10.1016/j.psychres.2017.11.033Search in Google Scholar PubMed

[65] Jeppesen R, Christensen RH, Pedersen EM, Nordentoft M, Hjorthøj C, Köhler-Forsberg O, et al. Efficacy and safety of anti-inflammatory agents in treatment of psychotic disorders – a comprehensive systematic review and meta-analysis. Brain Behav Immun. 2020 Nov;90:364–80.10.1016/j.bbi.2020.08.028Search in Google Scholar PubMed

[66] Çakici N, van Beveren NJ, Judge-Hundal G, Koola MM, Sommer IE. An update on the efficacy of anti-inflammatory agents for patients with schizophrenia: a meta-analysis. Psychol Med. 2019 Oct;49(14):2307–19.10.1017/S0033291719001995Search in Google Scholar PubMed PubMed Central

[67] Shen H, Li R, Yan R, Zhou X, Feng X, Zhao M, et al. Adjunctive therapy with statins in schizophrenia patients: a meta-analysis and implications. Psychiatry Res. 2018 Apr;262:84–93.10.1016/j.psychres.2018.02.018Search in Google Scholar PubMed

[68] Atil B, Berger-Sieczkowski E, Bardy J, Werner M, Hohenegger M. In vitro and in vivo downregulation of the ATP binding cassette transporter B1 by the HMG-CoA reductase inhibitor simvastatin. Naunyn Schmiedebergs Arch Pharmacol. 2016 Jan;389(1):17–32.10.1007/s00210-015-1169-3Search in Google Scholar PubMed PubMed Central

[69] Aquilante CL, Wempe MF, Sidhom MS, Kosmiski LA, Predhomme JA. Effect of ABCB1 polymorphisms and atorvastatin on sitagliptin pharmacokinetics in healthy volunteers. Eur J Clin Pharmacol. 2013 Jul;69(7):1401–9.10.1007/s00228-013-1475-ySearch in Google Scholar PubMed PubMed Central

[70] Wang E, Casciano CN, Clement RP, Johnson WW. HMG-CoA reductase inhibitors (statins) characterized as direct inhibitors of P-glycoprotein. Pharm Res. 2001 Jun;18(6):800–6.10.1023/A:1011036428972Search in Google Scholar

[71] García-Bueno B, Bioque M, Mac-Dowell KS, Barcones MF, Martínez-Cengotitabengoa M, Pina-Camacho L, et al. Pro-/anti-inflammatory dysregulation in patients with first episode of psychosis: toward an integrative inflammatory hypothesis of schizophrenia. Schizophr Bull. 2014 Mar;40(2):376–87.10.1093/schbul/sbt001Search in Google Scholar PubMed PubMed Central

[72] Goldsmith DR, Rapaport MH, Miller BJ. A meta-analysis of blood cytokine network alterations in psychiatric patients: comparisons between schizophrenia, bipolar disorder and depression. Mol Psychiatry. 2016 Dec;21(12):1696–709.10.1038/mp.2016.3Search in Google Scholar PubMed PubMed Central

[73] Fourrier C, Singhal G, Baune BT. Neuroinflammation and cognition across psychiatric conditions. CNS Spectr. 2019 Feb;24(1):4–15.10.1017/S1092852918001499Search in Google Scholar PubMed

[74] Barron H, Hafizi S, Andreazza AC, Mizrahi R. Neuroinflammation and oxidative stress in psychosis and psychosis risk. Int J Mol Sci. 2017 Mar;18(3):E651.10.3390/ijms18030651Search in Google Scholar PubMed PubMed Central

[75] Wei C, Sun Y, Chen N, Chen S, Xiu M, Zhang X. Interaction of oxidative stress and BDNF on executive dysfunction in patients with chronic schizophrenia. Psychoneuroendocrinology. 2020 Jan;111:104473.10.1016/j.psyneuen.2019.104473Search in Google Scholar PubMed

[76] Kim SW, Kang HJ, Jhon M, Kim JW, Lee JY, Walker AJ, et al. Statins and inflammation: new therapeutic opportunities in psychiatry. Front Psychiatry. 2019 Mar;10:103.10.3389/fpsyt.2019.00103Search in Google Scholar PubMed PubMed Central

[77] Fracassi A, Marangoni M, Rosso P, Pallottini V, Fioramonti M, Siteni S, et al. Statins and the brain: more than lipid lowering agents? Curr Neuropharmacol. 2019;17(1):59–83.10.2174/1570159X15666170703101816Search in Google Scholar PubMed PubMed Central

[78] Barbosa IG, Bauer ME, Machado-Vieira R, Teixeira AL. Cytokines in bipolar disorder: paving the way for neuroprogression. Neural Plast. 2014;2014:360481.10.1155/2014/360481Search in Google Scholar PubMed PubMed Central

[79] Rosenblat JD, McIntyre RS. Bipolar disorder and immune dysfunction: epidemiological findings, proposed pathophysiology and clinical implications. Brain Sci. 2017 Oct;7(11):E144.10.3390/brainsci7110144Search in Google Scholar PubMed PubMed Central

[80] Sayana P, Colpo GD, Simões LR, Giridharan VV, Teixeira AL, Quevedo J, et al. A systematic review of evidence for the role of inflammatory biomarkers in bipolar patients. J Psychiatr Res. 2017 Sep;92:160–82.10.1016/j.jpsychires.2017.03.018Search in Google Scholar PubMed

[81] Tonin PT, Valvassori SS, Lopes-Borges J, Mariot E, Varela RB, Teixeira AL, et al. Effects of ouabain on cytokine/chemokine levels in an animal model of mania. J Neuroimmunol. 2014 Nov;276(1–2):236–9.10.1016/j.jneuroim.2014.09.007Search in Google Scholar PubMed

[82] Valvassori SS, Dal-Pont GC, Tonin PT, Varela RB, Ferreira CL, Gava FF, et al. Coadministration of lithium and celecoxib attenuates the behavioral alterations and inflammatory processes induced by amphetamine in an animal model of mania. Pharmacol Biochem Behav. 2019 Aug;183:56–63.10.1016/j.pbb.2019.05.009Search in Google Scholar PubMed

[83] Valvassori SS, Resende WR, Dal-Pont G, Sangaletti-Pereira H, Gava FF, Peterle BR, et al. Lithium ameliorates sleep deprivation-induced mania-like behavior, hypothalamic-pituitary-adrenal (HPA) axis alterations, oxidative stress and elevations of cytokine concentrations in the brain and serum of mice. Bipolar Disord. 2017 Jun;19(4):246–58.10.1111/bdi.12503Search in Google Scholar PubMed

[84] Valvassori SS, Tonin PT, Varela RB, Carvalho AF, Mariot E, Amboni RT, et al. Lithium modulates the production of peripheral and cerebral cytokines in an animal model of mania induced by dextroamphetamine. Bipolar Disord. 2015 Aug;17(5):507–17.10.1111/bdi.12299Search in Google Scholar PubMed

[85] Rudkin TM, Arnold DL. Proton magnetic resonance spectroscopy for the diagnosis and management of cerebral disorders. Arch Neurol. 1999 Aug;56(8):919–26.10.1001/archneur.56.8.919Search in Google Scholar PubMed

[86] Magioncalda P, Martino M, Tardito S, Sterlini B, Conio B, Marozzi V, et al. White matter microstructure alterations correlate with terminally differentiated CD8 + effector T cell depletion in the peripheral blood in mania: combined DTI and immunological investigation in the different phases of bipolar disorder. Brain Behav Immun. 2018 Oct;73:192–204.10.1016/j.bbi.2018.04.017Search in Google Scholar PubMed

[87] Barbosa IG, Rocha NP, Huguet RB, Ferreira RA, Salgado JV, Carvalho LA, et al. Executive dysfunction in euthymic bipolar disorder patients and its association with plasma biomarkers. J Affect Disord. 2012 Mar;137(1–3):151–5.10.1016/j.jad.2011.12.034Search in Google Scholar PubMed

[88] Hope S, Hoseth E, Dieset I, Mørch RH, Aas M, Aukrust P, et al. Inflammatory markers are associated with general cognitive abilities in schizophrenia and bipolar disorder patients and healthy controls. Schizophr Res. 2015 Jul;165(2–3):188–94.10.1016/j.schres.2015.04.004Search in Google Scholar PubMed

[89] Bauer IE, Pascoe MC, Wollenhaupt-Aguiar B, Kapczinski F, Soares JC. Inflammatory mediators of cognitive impairment in bipolar disorder. J Psychiatr Res. 2014 Sep;56:18–27.10.1016/j.jpsychires.2014.04.017Search in Google Scholar PubMed PubMed Central

[90] Rosenblat JD, Brietzke E, Mansur RB, Maruschak NA, Lee Y, McIntyre RS. Inflammation as a neurobiological substrate of cognitive impairment in bipolar disorder: evidence, pathophysiology and treatment implications. J Affect Disord. 2015 Dec;188:149–59.10.1016/j.jad.2015.08.058Search in Google Scholar PubMed

[91] Giridharan VV, Sayana P, Pinjari OF, Ahmad N, da Rosa MI, Quevedo J, et al. Postmortem evidence of brain inflammatory markers in bipolar disorder: a systematic review. Mol Psychiatry. 2020 Jan;25(1):94–113.10.1038/s41380-019-0448-7Search in Google Scholar PubMed

[92] Bortolato B, Miskowiak KW, Köhler CA, Vieta E, Carvalho AF. Cognitive dysfunction in bipolar disorder and schizophrenia: a systematic review of meta-analyses. Neuropsychiatr Dis Treat. 2015 Dec;11:3111–25.10.2147/NDT.S76700Search in Google Scholar PubMed PubMed Central

[93] Bo Q, Tian L, Li F, Mao Z, Wang Z, Ma X, et al. Quality of life in euthymic patients with unipolar major depressive disorder and bipolar disorder. Neuropsychiatr Dis Treat. 2019 Jun;15:1649–57.10.2147/NDT.S201567Search in Google Scholar PubMed PubMed Central

[94] Leboyer M, Kupfer DJ. Bipolar disorder: new perspectives in health care and prevention. J Clin Psychiatry. 2010 Dec;71(12):1689–95.10.4088/JCP.10m06347yelSearch in Google Scholar PubMed PubMed Central

[95] Knežević V, Nedić A. Influence of misdiagnosis on the course of bipolar disorder. Eur Rev Med Pharmacol Sci. 2013 Jun;17(11):1542–5.Search in Google Scholar

[96] Muneer A. Staging models in bipolar disorder: a systematic review of the literature. Clin Psychopharmacol Neurosci. 2016 May;14(2):117–30.10.9758/cpn.2016.14.2.117Search in Google Scholar PubMed PubMed Central

[97] Berk M. Neuroprogression: pathways to progressive brain changes in bipolar disorder. Int J Neuropsychopharmacol. 2009 May;12(4):441–5.10.1017/S1461145708009498Search in Google Scholar PubMed

[98] Berk M, Berk L, Dodd S, Cotton S, Macneil C, Daglas R, et al. Stage managing bipolar disorder. Bipolar Disord. 2014 Aug;16(5):471–7.10.1111/bdi.12099Search in Google Scholar PubMed

[99] Fries GR, Pfaffenseller B, Stertz L, Paz AV, Dargél AA, Kunz M, et al. Staging and neuroprogression in bipolar disorder. Curr Psychiatry Rep. 2012 Dec;14(6):667–75.10.1007/s11920-012-0319-2Search in Google Scholar PubMed

[100] Berk M, Kapczinski F, Andreazza AC, Dean OM, Giorlando F, Maes M, et al. Pathways underlying neuroprogression in bipolar disorder: focus on inflammation, oxidative stress and neurotrophic factors. Neurosci Biobehav Rev. 2011 Jan;35(3):804–17.10.1016/j.neubiorev.2010.10.001Search in Google Scholar PubMed

[101] Gama CS, Kunz M, Magalhães PV, Kapczinski F. Staging and neuroprogression in bipolar disorder: a systematic review of the literature. Br J Psychiatry. 2013 Mar;35(1):70–4.10.1016/j.rbp.2012.09.001Search in Google Scholar PubMed

[102] Schneider MR, DelBello MP, McNamara RK, Strakowski SM, Adler CM. Neuroprogression in bipolar disorder. Bipolar Disord. 2012 Jun;14(4):356–74.10.1111/j.1399-5618.2012.01024.xSearch in Google Scholar PubMed

[103] Post RM, Fleming J, Kapczinski F. Neurobiological correlates of illness progression in the recurrent affective disorders. J Psychiatr Res. 2012 May;46(5):561–73.10.1016/j.jpsychires.2012.02.004Search in Google Scholar PubMed

[104] Kapczinski F, Vieta E, Andreazza AC, Frey BN, Gomes FA, Tramontina J, et al. Allostatic load in bipolar disorder: implications for pathophysiology and treatment. Neurosci Biobehav Rev. 2008;32(4):675–92.10.1016/j.neubiorev.2007.10.005Search in Google Scholar PubMed

[105] Sajatovic M, Strejilevich SA, Gildengers AG, Dols A, Al Jurdi RK, Forester BP, et al. A report on older-age bipolar disorder from the International Society for Bipolar Disorders Task Force. Bipolar Disord. 2015 Nov;17(7):689–704.10.1111/bdi.12331Search in Google Scholar PubMed PubMed Central

[106] Sublette ME, Postolache TT. Neuroinflammation and depression: the role of indoleamine 2,3-dioxygenase (IDO) as a molecular pathway. Psychosom Med. 2012 Sep;74(7):668–72.10.1097/PSY.0b013e318268de9fSearch in Google Scholar PubMed

[107] Sublette ME, Galfalvy HC, Fuchs D, Lapidus M, Grunebaum MF, Oquendo MA, et al. Plasma kynurenine levels are elevated in suicide attempters with major depressive disorder. Brain Behav Immun. 2011 Aug;25(6):1272–8.10.1016/j.bbi.2011.05.002Search in Google Scholar PubMed PubMed Central

[108] Brundin L, Sellgren CM, Lim CK, Grit J, Pålsson E, Landén M, et al. An enzyme in the kynurenine pathway that governs vulnerability to suicidal behavior by regulating excitotoxicity and neuroinflammation. Transl Psychiatry. 2016 Aug;6(8):e865.10.1038/tp.2016.133Search in Google Scholar PubMed PubMed Central

[109] Erhardt S, Lim CK, Linderholm KR, Janelidze S, Lindqvist D, Samuelsson M, et al. Connecting inflammation with glutamate agonism in suicidality. Neuropsychopharmacology. 2013 Apr;38(5):743–52.10.1038/npp.2012.248Search in Google Scholar PubMed PubMed Central

[110] Plitman E, Iwata Y, Caravaggio F, Nakajima S, Chung JK, Gerretsen P, et al. Kynurenic acid in schizophrenia: a systematic review and meta-analysis. Schizophr Bull. 2017 Jul;43(4):764–77.10.1093/schbul/sbw221Search in Google Scholar PubMed PubMed Central

[111] Linderholm KR, Skogh E, Olsson SK, Dahl ML, Holtze M, Engberg G, et al. Increased levels of kynurenine and kynurenic acid in the CSF of patients with schizophrenia. Schizophr Bull. 2012 May;38(3):426–32.10.1093/schbul/sbq086Search in Google Scholar PubMed PubMed Central

[112] Sellgren CM, Gracias J, Jungholm O, Perlis RH, Engberg G, Schwieler L, et al. Peripheral and central levels of kynurenic acid in bipolar disorder subjects and healthy controls. Transl Psychiatry. 2019 Jan;9(1):37.10.1038/s41398-019-0378-9Search in Google Scholar PubMed PubMed Central

[113] Cathomas F, Guetter K, Seifritz E, Klaus F, Kaiser S. Quinolinic acid is associated with cognitive deficits in schizophrenia but not major depressive disorder. Sci Rep. 2021 May;11(1):9992.10.1038/s41598-021-89335-9Search in Google Scholar PubMed PubMed Central

[114] Zhang P, Huang H, Gao X, Jiang J, Xi C, Wu L, et al. Involvement of kynurenine metabolism in bipolar disorder: an updated review. Front Psychiatry. 2021 Jul;12:677039.10.3389/fpsyt.2021.677039Search in Google Scholar PubMed PubMed Central

[115] Mukherjee D, Krishnamurthy VB, Millett CE, Reider A, Can A, Groer M, et al. Total sleep time and kynurenine metabolism associated with mood symptom severity in bipolar disorder. Bipolar Disord. 2018 Feb;20(1):27–34.10.1111/bdi.12529Search in Google Scholar PubMed PubMed Central

[116] Neurauter G, Wirleitner B, Laich A, Schennach H, Weiss G, Fuchs D. Atorvastatin suppresses interferon-gamma -induced neopterin formation and tryptophan degradation in human peripheral blood mononuclear cells and in monocytic cell lines. Clin Exp Immunol. 2003 Feb;131(2):264–7.10.1046/j.1365-2249.2003.02021.xSearch in Google Scholar PubMed PubMed Central

[117] Dhar I, Siddique S, Pedersen ER, Svingen GF, Lysne V, Olsen T, et al. Lipid parameters and vitamin A modify cardiovascular risk prediction by plasma neopterin. Heart. 2020 Jul;106(14):1073–9.10.1136/heartjnl-2019-316165Search in Google Scholar PubMed

[118] Ray KK, Morrow DA, Sabatine MS, Shui A, Rifai N, Cannon CP, et al. Long-term prognostic value of neopterin: a novel marker of monocyte activation in patients with acute coronary syndrome. Circulation. 2007 Jun;115(24):3071–8.10.1161/CIRCULATIONAHA.106.666511Search in Google Scholar PubMed

[119] Azor MH, dos Santos JC, Futata EA, de Brito CA, Maruta CW, Rivitti EA, et al. Statin effects on regulatory and proinflammatory factors in chronic idiopathic urticaria. Clin Exp Immunol. 2011 Nov;166(2):291–8.10.1111/j.1365-2249.2011.04473.xSearch in Google Scholar PubMed PubMed Central

[120] De Jong HJ, Damoiseaux JG, Vandebriel RJ, Souverein PC, Gremmer ER, Wolfs M, et al. Statin use and markers of immunity in the Doetinchem cohort study. PLoS One. 2013 Oct;8(10):e77587.10.1371/journal.pone.0077587Search in Google Scholar PubMed PubMed Central

[121] Mulder DJ, van Haelst PL, Wobbes MH, Gans RO, Zijlstra F, May JF, et al. The effect of aggressive versus conventional lipid-lowering therapy on markers of inflammatory and oxidative stress. Cardiovasc Drugs Ther. 2007 Apr;21(2):91–7.10.1007/s10557-007-6010-xSearch in Google Scholar PubMed PubMed Central

[122] Lee KJ, Moon JY, Choi HK, Kim HO, Hur GY, Jung KH, et al. Immune regulatory effects of simvastatin on regulatory T cell-mediated tumour immune tolerance. Clin Exp Immunol. 2010 Aug;161(2):298–305.10.1111/j.1365-2249.2010.04170.xSearch in Google Scholar PubMed PubMed Central

[123] Forero-Peña DA, Gutierrez FR. Statins as modulators of regulatory T-cell biology. Mediators Inflamm. 2013;2013:167086.10.1155/2013/167086Search in Google Scholar PubMed PubMed Central

[124] Rodríguez-Perea AL, Montoya CJ, Olek S, Chougnet CA, Velilla PA. Statins increase the frequency of circulating CD4 + FOXP3 + regulatory T cells in healthy individuals. J Immunol Res. 2015;2015:762506.10.1155/2015/762506Search in Google Scholar PubMed PubMed Central

[125] Saksida T, Jevtić B, Djedović N, Miljković Đ, Stojanović I. Redox Regulation of tolerogenic dendritic cells and regulatory T cells in the pathogenesis and therapy of autoimmunity. Antioxid Redox Signal. 2021 Feb;34(5):364–82.10.1089/ars.2019.7999Search in Google Scholar PubMed

[126] Kalonia H, Kumar P, Kumar A. Comparative neuroprotective profile of statins in quinolinic acid induced neurotoxicity in rats. Behav Brain Res. 2011 Jan;216(1):220–8.10.1016/j.bbr.2010.07.040Search in Google Scholar PubMed

[127] Piermartiri TC, Vandresen-Filho S, de Araújo Herculano B, Martins WC, Dal’agnolo D, Stroeh E, et al. Atorvastatin prevents hippocampal cell death due to quinolinic acid-induced seizures in mice by increasing Akt phosphorylation and glutamate uptake. Neurotox Res. 2009 Aug;16(2):106–15.10.1007/s12640-009-9057-6Search in Google Scholar PubMed

[128] Vandresen-Filho S, Martins WC, Bertoldo DB, Rieger DK, Maestri M, Leal RB, et al. Atorvastatin prevents glutamate uptake reduction induced by quinolinic acid via MAPKs signaling. Neurochem Res. 2016 Aug;41(8):2017–28.10.1007/s11064-016-1913-1Search in Google Scholar PubMed

[129] Yebyo HG, Aschmann HE, Kaufmann M, Puhan MA. Comparative effectiveness and safety of statins as a class and of specific statins for primary prevention of cardiovascular disease: a systematic review, meta-analysis, and network meta-analysis of randomized trials with 94,283 participants. Am Heart J. 2019 Apr;210:18–28.10.1016/j.ahj.2018.12.007Search in Google Scholar PubMed

[130] Sierra S, Ramos MC, Molina P, Esteo C, Vázquez JA, Burgos JS. Statins as neuroprotectants: a comparative in vitro study of lipophilicity, blood-brain-barrier penetration, lowering of brain cholesterol, and decrease of neuron cell death. J Alzheimers Dis. 2011;23(2):307–18.10.3233/JAD-2010-101179Search in Google Scholar PubMed

[131] Lilly SM, Mortensen EM, Frei CR, Pugh MJ, Mansi IA. Comparison of the risk of psychological and cognitive disorders between persistent and nonpersistent statin users. Am J Cardiol. 2014 Oct;114(7):1035–9.10.1016/j.amjcard.2014.07.010Search in Google Scholar PubMed

[132] Song Y, Nie H, Xu Y, Zhang L, Wu Y. Association of statin use with risk of dementia: a meta-analysis of prospective cohort studies. Geriatr Gerontol Int. 2013 Oct;13(4):817–24.10.1111/ggi.12044Search in Google Scholar PubMed

[133] Xuan K, Zhao T, Qu G, Liu H, Chen X, Sun Y. The efficacy of statins in the treatment of Alzheimer’s disease: a meta-analysis of randomized controlled trial. Neurol Sci. 2020 Jun;41(6):1391–404.10.1007/s10072-020-04243-6Search in Google Scholar

[134] Köhler O, Gasse C, Petersen L, Ingstrup KG, Nierenberg AA, Mors O, et al. The effect of concomitant treatment with SSRIs and statins: a population-based study. Am J Psychiatry. 2016 Aug;173(8):807–15.10.1176/appi.ajp.2016.15040463Search in Google Scholar

[135] Weiser M, Davis JM, Brown CH, Slade EP, Fang LJ, Medoff DR, et al. Differences in antipsychotic treatment discontinuation among Veterans with Schizophrenia in the U.S. Department of Veterans Affairs. Am J Psychiatry. 2021 Jul 14; appiajp202020111657. 10.1176/appi.ajp.2020.20111657.Search in Google Scholar

[136] Yelland LN, Salter AB, Ryan P. Performance of the modified Poisson regression approach for estimating relative risks from clustered prospective data. Am J Epidemiol. 2011 Oct;174(8):984–92.10.1093/aje/kwr183Search in Google Scholar

[137] Andrade C. Relative to SSRI users, SSRI-statin users have fewer psychiatric hospital contacts and no increase in suicidal behaviour or all-cause mortality. Evid Based Ment Health. 2017 May;20(2):60.10.1136/eb-2016-102566Search in Google Scholar

[138] Davison KM, Kaplan BJ. Lipophilic statin use and suicidal ideation in a sample of adults with mood disorders. Crisis. 2014 Jan;35(4):278–82.10.1027/0227-5910/a000260Search in Google Scholar

[139] Muldoon MF, Barger SD, Ryan CM, Flory JD, Lehoczky JP, Matthews KA, et al. Effects of lovastatin on cognitive function and psychological well-being. Am J Med. 2000 May;108(7):538–46.10.1016/S0002-9343(00)00353-3Search in Google Scholar

[140] Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981 Aug;30(2):239–45.10.1038/clpt.1981.154Search in Google Scholar PubMed

[141] Roth T, Richardson GR, Sullivan JP, Lee RM, Merlotti L, Roehrs T. Comparative effects of pravastatin and lovastatin on nighttime sleep and daytime performance. Clin Cardiol. 1992 Jun;15(6):426–32.10.1002/clc.4960150607Search in Google Scholar PubMed

[142] Takada M, Fujimoto M, Yamazaki K, Takamoto M, Hosomi K. Association of statin use with sleep disturbances: data mining of a spontaneous reporting database and a prescription database. Drug Saf. 2014 Jun;37(6):421–31. Erratum in: Drug Saf. 2014 Aug;37(8):653.10.1007/s40264-014-0163-xSearch in Google Scholar PubMed

[143] Ott BR, Daiello LA, Dahabreh IJ, Springate BA, Bixby K, Murali M, et al. Do statins impair cognition? A systematic review and meta-analysis of randomized controlled trials. J Gen Intern Med. 2015 Mar;30(3):348–58.10.1007/s11606-014-3115-3Search in Google Scholar PubMed PubMed Central

[144] Swiger KJ, Manalac RJ, Blumenthal RS, Blaha MJ, Martin SS. Statins and cognition: a systematic review and meta-analysis of short- and long-term cognitive effects. Mayo Clin Proc. 2013 Nov;88(11):1213–21.10.1016/j.mayocp.2013.07.013Search in Google Scholar PubMed

[145] Broncel M, Gorzelak-Pabiś P, Sahebkar A, Serejko K, Ursoniu S, Rysz J, et al. Lipid and Blood Pressure Meta-analysis Collaboration (LBPMC) Group. Sleep changes following statin therapy: a systematic review and meta-analysis of randomized placebo-controlled polysomnographic trials. Arch Med Sci. 2015 Oct;11(5):915–26.Search in Google Scholar

[146] Nadkarni NK, Perera S, Hanlon JT, Lopez O, Newman AB, Aizenstein H, et al. Statins and brain integrity in older adults: secondary analysis of the Health ABC study. Alzheimers Dement. 2015 Oct;11(10):1202–11.10.1016/j.jalz.2014.11.003Search in Google Scholar PubMed PubMed Central

[147] Rej S, Schulte SW, Rajji TK, Gildengers AG, Miranda D, Menon M, et al. Statins and cognition in late-life bipolar disorder. Int J Geriatr Psychiatry. 2018 Oct;33(10):1355–60.10.1002/gps.4956Search in Google Scholar PubMed

[148] Tsai SY, Kuo CJ, Chung KH, Huang YL, Lee HC, Chen CC. Cognitive dysfunction and medical morbidity in elderly outpatients with bipolar disorder. Am J Geriatr Psychiatry. 2009 Dec;17(12):1004–11.10.1097/JGP.0b013e3181b7ef2aSearch in Google Scholar PubMed

[149] Bernick C, Katz R, Smith NL, Rapp S, Bhadelia R, Carlson M, et al.; Cardiovascular Health Study Collaborative Research Group. Statins and cognitive function in the elderly: the Cardiovascular Health Study. Neurology. 2005 Nov;65(9):1388–94.10.1212/01.wnl.0000182897.18229.ecSearch in Google Scholar PubMed

[150] Etminan M, Gill S, Samii A. The role of lipid-lowering drugs in cognitive function: a meta-analysis of observational studies. Pharmacotherapy. 2003 Jun;23(6):726–30.10.1592/phco.23.6.726.32184Search in Google Scholar PubMed

[151] Sparks DL, Kryscio RJ, Sabbagh MN, Connor DJ, Sparks LM, Liebsack C. Reduced risk of incident AD with elective statin use in a clinical trial cohort. Curr Alzheimer Res. 2008 Aug;5(4):416–21.10.2174/156720508785132316Search in Google Scholar PubMed

[152] Xu X, Gao W, Cheng S, Yin D, Li F, Wu Y, et al. Anti-inflammatory and immunomodulatory mechanisms of atorvastatin in a murine model of traumatic brain injury. J Neuroinflamm. 2017 Aug;14(1):167.10.1186/s12974-017-0934-2Search in Google Scholar PubMed PubMed Central

[153] Torrey EF, Bartko JJ, Lun ZR, Yolken RH. Antibodies to Toxoplasma gondii in patients with schizophrenia: a meta-analysis. Schizophr Bull. 2007 May;33(3):729–36.10.1093/schbul/sbl050Search in Google Scholar PubMed PubMed Central

[154] Arling TA, Yolken RH, Lapidus M, Langenberg P, Dickerson FB, Zimmerman SA, et al. Toxoplasma gondii antibody titers and history of suicide attempts in patients with recurrent mood disorders. J Nerv Ment Dis. 2009 Dec;197(12):905–8.10.1097/NMD.0b013e3181c29a23Search in Google Scholar PubMed

[155] Fan QW, Yu W, Senda T, Yanagisawa K, Michikawa M. Cholesterol-dependent modulation of tau phosphorylation in cultured neurons. J Neurochem. 2001 Jan;76(2):391–400.10.1046/j.1471-4159.2001.00063.xSearch in Google Scholar PubMed

[156] Asellus P, Nordström P, Jokinen J. Cholesterol and CSF 5-HIAA in attempted suicide. J Affect Disord. 2010 Sep;125(1–3):388–92.10.1016/j.jad.2010.02.111Search in Google Scholar PubMed

[157] De Berardis D, Conti CM, Serroni N, Moschetta FS, Carano A, Salerno RM, et al. The role of cholesterol levels in mood disorders and suicide. J Biol Regul Homeost Agents. 2009 Jul-Sep;23(3):133–40.Search in Google Scholar

[158] Shrivastava S, Pucadyil TJ, Paila YD, Ganguly S, Chattopadhyay A. Chronic cholesterol depletion using statin impairs the function and dynamics of human serotonin(1A) receptors. Biochemistry. 2010 Jul;49(26):5426–35.10.1021/bi100276bSearch in Google Scholar PubMed

[159] Mendoza-Oliva A, Zepeda A, Arias C. The complex actions of statins in brain and their relevance for Alzheimer’s disease treatment: an analytical review. Curr Alzheimer Res. 2014;11(9):817–33.10.2174/1567205011666141001114858Search in Google Scholar

[160] Mendoza-Oliva A, Ferrera P, Arias C. Interplay between cholesterol and homocysteine in the exacerbation of amyloid-β toxicity in human neuroblastoma cells. CNS Neurol Disord Drug Targets. 2013 Sep;12(6):842–8.10.2174/18715273113129990083Search in Google Scholar PubMed

[161] Marcuzzi A, Tricarico PM, Piscianz E, Kleiner G, Vecchi Brumatti L, Crovella S. Lovastatin induces apoptosis through the mitochondrial pathway in an undifferentiated SH-SY5Y neuroblastoma cell line. Cell Death Dis. 2013 Apr;4(4):e585.10.1038/cddis.2013.112Search in Google Scholar PubMed PubMed Central

[162] Cui F, Gu S, Gu Y, Yin J, Fang C, Liu L. Alteration in the mRNA expression profile of the autophagy-related mTOR pathway in schizophrenia patients treated with olanzapine. BMC Psychiatry. 2021 Aug;21(1):388.10.1186/s12888-021-03394-wSearch in Google Scholar PubMed PubMed Central

[163] Kang SY, Lee SB, Kim HJ, Kim HT, Yang HO, Jang W. Autophagic modulation by rosuvastatin prevents rotenone-induced neurotoxicity in an in vitro model of Parkinson’s disease. Neurosci Lett. 2017 Mar;642:20–6.10.1016/j.neulet.2017.01.063Search in Google Scholar PubMed

[164] Bellosta S, Corsini A. Statin drug interactions and related adverse reactions. Expert Opin Drug Saf. 2012 Nov;11(6):933–46.10.1517/14740338.2012.712959Search in Google Scholar PubMed

[165] Paoletti R, Corsini A, Bellosta S. Pharmacological interactions of statins. Atheroscler Suppl. 2002 May;3(1):35–40.10.1016/S1567-5688(02)00002-8Search in Google Scholar

[166] Athyros VG, Katsiki N, Karagiannis A, Mikhailidis DP. High-intensity statin therapy and regression of coronary atherosclerosis in patients with diabetes mellitus. J Diabetes Compl. 2015 Jan–Feb;29(1):142–5.10.1016/j.jdiacomp.2014.10.004Search in Google Scholar PubMed

[167] Khemasuwan D, Chae YK, Gupta S, Carpio A, Yun JH, Neagu S, et al. Dose-related effect of statins in venous thrombosis risk reduction. Am J Med. 2011 Sep;124(9):852–9.10.1016/j.amjmed.2011.04.019Search in Google Scholar PubMed

[168] Karageorgiou V, Milas GP, Michopoulos I. Neutrophil-to-lymphocyte ratio in schizophrenia: A systematic review and meta-analysis. Schizophr Res. 2019 Apr;206:4–12.10.1016/j.schres.2018.12.017Search in Google Scholar PubMed

[169] Fusar-Poli L, Natale A, Amerio A, Cimpoesu P, Grimaldi Filioli P, Aguglia E, et al. Neutrophil-to-lymphocyte, platelet-to-lymphocyte and monocyte-to-lymphocyte ratio in bipolar disorder. Brain Sci. 2021 Jan;11(1):58.10.3390/brainsci11010058Search in Google Scholar PubMed PubMed Central

[170] Sağlam Aykut D, Civil Arslan F, Özkorumak Karagüzel E, Aral G, Karakullukçu S. The relationship between neutrophil-lymphocyte, platelet-lymphocyte ratio and cognitive functions in bipolar disorder. Nord J Psychiatry. 2018 Feb;72(2):119–23.10.1080/08039488.2017.1397192Search in Google Scholar PubMed

[171] Zhang J, Shi X, Hao N, Chen Z, Wei L, Tan L, et al. Simvastatin reduces neutrophils infiltration into brain parenchyma after intracerebral hemorrhage via regulating peripheral neutrophils apoptosis. Front Neurosci. 2018 Dec;12:977.10.3389/fnins.2018.00977Search in Google Scholar PubMed PubMed Central

Received: 2021-08-23
Revised: 2021-09-01
Accepted: 2021-09-01
Published Online: 2021-09-23

© 2021 Teodor T. Postolache et al., published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

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