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

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.

Is It Time for a Paradigm Shift in the Treatment of Schizophrenia? The Use of Inflammation-Reducing and Neuroprotective Drugs—A Review

“…Nevertheless, not all studies agree: some authors came to opposite conclusions of no efficacy [ 43 , 44 ], and in a meta-analysis, statins were not reported to be effective in controlling the severity of schizophrenia symptoms, regardless of the molecule’s tendency to pass the BBB [ 18 ]. In a large retrospective study performed on veterans with schizophrenia, the authors observed that the risk of incurring hospitalization was lower in patients taking statins [ 45 ]. The effect of statins may be due to their effect in reducing neuroinflammation [ 46 ], and decreasing blood values of IL-1β, IL-6, TNF-α, and C-reactive protein (CRP) [ 46 , 47 ].…”

Augmentation Therapies as Treatments for Coexisting Somatic Problems in Schizophrenia—A Systematic Review

“…It has been noted that their use in patients with schizophrenia may reduce the severity of negative symptoms, but the differences are not statistically significant [ 23 , 29 , 30 ]. The anti-inflammatory effect of statins works by reducing the production of inflammatory cytokines, such as interleukin 1-β (IL1-β), interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), and C-reactive protein (CRP) [ 67 , 68 , 69 ], and it is hypothesized that the lipophilicity of statins improves the effects of treatment with antipsychotic drugs. Simvastatin and atorvastatin have shown a greater ability to cross the blood-brain barrier compared to rosuvastatin and pravastatin.…”

The COVID-19 "Bad Tryp" Syndrome: NAD/NADH+, Tryptophan Phenylalanine Metabolism and Thermogenesis like Hecatomb - The Hypothesis of Pathophysiology Based on a Compared COVID-19 and Yellow Fever Inflammatory Skeleton

“…IL-1β, interferon-γ and TNF-α, can induce both GCH1 expression and activity, therefore increasing BH4 synthesis. At the post-translational level, GCH1 is inhibited by BH4 and stimulated by phenylalanine [153][154][155][156].…”