Camacho Mariam B, Vijitbenjaronk Warut D, Anastasio Thomas J
Computational Neurobiology Laboratory, Neuroscience Program, Medical Scholars Program, University of Illinois College of Medicine at Urbana-Champaign, Urbana, IL, United States.
Computational Neurobiology Laboratory, Department of Computer Science, University of Illinois at Urbana-Champaign, Urbana, IL, United States.
Front Pharmacol. 2019 Oct 25;10:1215. doi: 10.3389/fphar.2019.01215. eCollection 2019.
The clinical practice of selective serotonin reuptake inhibitor (SSRI) augmentation relies heavily on trial-and-error. Unfortunately, the drug combinations prescribed today fail to provide relief for many depressed patients. In order to identify potentially more effective treatments, we developed a computational model of the monoaminergic neurotransmitter and stress-steroid systems that neuroadapts to chronic administration of combinations of antidepressant drugs and hormones by adjusting the strengths of its transmitter-system components (TSCs). We used the model to screen 60 chronically administered drug/hormone pairs and triples, and identified as potentially therapeutic those combinations that raised the monoamines (serotonin, norepinephrine, and dopamine) but lowered cortisol following neuroadaptation in the model. We also evaluated the contributions of individual and pairs of TSCs to therapeutic neuroadaptation with chronic SSRI using sensitivity, correlation, and linear temporal-logic analyses. All three approaches revealed that therapeutic neuroadaptation to chronic SSRI is an overdetermined process that depends on multiple TSCs, providing a potential explanation for the clinical finding that no single antidepressant regimen alleviates depressive symptoms in all patients.
选择性5-羟色胺再摄取抑制剂（SSRI）增效的临床实践在很大程度上依赖反复试验。遗憾的是，如今所开的药物组合无法为许多抑郁症患者缓解症状。为了确定可能更有效的治疗方法，我们开发了一种单胺能神经递质和应激类固醇系统的计算模型，该模型通过调整其递质系统组件（TSC）的强度来对长期使用的抗抑郁药物和激素组合产生神经适应性变化。我们使用该模型筛选了60种长期使用的药物/激素对和三联组合，并确定那些在模型中产生神经适应性变化后能提高单胺类物质（5-羟色胺、去甲肾上腺素和多巴胺）但降低皮质醇水平的组合具有潜在治疗作用。我们还使用敏感性、相关性和线性时间逻辑分析评估了单个TSC和TSC对在长期使用SSRI治疗时产生治疗性神经适应性变化的贡献。所有这三种方法都表明，对长期使用SSRI产生的治疗性神经适应性变化是一个由多个因素决定的过程，这取决于多个TSC，这为临床上没有单一抗抑郁治疗方案能缓解所有患者抑郁症状这一发现提供了一个潜在的解释。
