Munroe-Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Center, Omaha, Nebraska, USA; Faculty of Medicine, Department of Medical Biology and Genetics, J. J. Strossmayer University of Osijek, Osijek, Croatia.
Munroe-Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Center, Omaha, Nebraska, USA.
J Lipid Res. 2022 Aug;63(8):100249. doi: 10.1016/j.jlr.2022.100249. Epub 2022 Jul 14.
Polypharmacy, or the simultaneous use of multiple drugs to treat a single patient, is a common practice in psychiatry. Unfortunately, data on the health effects of commonly used combinations of medications are very limited. In this study, we therefore investigated the effects and interactions between two commonly prescribed psychotropic medications with sterol inhibiting side effects, trazodone (TRZ), an antidepressant, and aripiprazole (ARI), an antipsychotic. In vitro cell culture experiments revealed that both medications alone disrupted neuronal and astroglial sterol biosynthesis in dose-dependent manners. Furthermore, when ARI and TRZ were combined, exposure resulted in an additive 7-dehydrocholesterol (7-DHC) increase, as well as desmosterol (DES) and cholesterol decreases in both cell types. In adult mice, at baseline, we found that the three investigated sterols showed significant differences in distribution across the eight assessed brain regions. Furthermore, experimental mice treated with ARI or TRZ, or a combination of both medications for 8 days, showed strong sterol disruption across all brain regions. We show ARI or TRZ alone elevated 7-DHC and decreased DES levels in all brain regions, but with regional differences. However, the combined utilization of these two medications for 8 days did not lead to additive changes in sterol disturbances. Based on the complex roles of 7-DHC derived oxysterols, we conclude that individual and potentially simultaneous use of medications with sterol biosynthesis-inhibiting properties might have undesired side effects on the adult brain, with as yet unknown long-term consequences on mental or physical health.
多药治疗，即同时使用多种药物治疗单一患者，是精神病学中的常见做法。不幸的是，关于常用药物组合对健康影响的数据非常有限。因此，在这项研究中，我们调查了两种具有固醇抑制副作用的常用精神药物（曲唑酮（TRZ），一种抗抑郁药和阿立哌唑（ARI），一种抗精神病药）之间的相互作用和影响。体外细胞培养实验表明，这两种药物单独使用时均以剂量依赖性方式破坏神经元和神经胶质固醇生物合成。此外，当 ARI 和 TRZ 联合使用时，暴露会导致 7-去氢胆固醇（7-DHC）的增加，以及两种细胞类型中 desmosterol（DES）和胆固醇的减少。在成年小鼠中，在基线时，我们发现三种研究中的固醇在分布在 8 个评估的脑区之间存在显著差异。此外，用 ARI 或 TRZ 或两种药物的组合处理 8 天的实验小鼠，在所有脑区均表现出强烈的固醇破坏。我们表明，ARI 或 TRZ 单独使用会导致所有脑区中的 7-DHC 升高和 DES 水平降低，但存在区域差异。然而，这两种药物联合使用 8 天并没有导致固醇紊乱的相加变化。基于 7-DHC 衍生的氧化固醇的复杂作用，我们得出结论，具有固醇生物合成抑制特性的药物的单独和潜在同时使用可能会对成年大脑产生不良的副作用，对精神或身体健康产生未知的长期影响。
