Gutiérrez-Casares José Ramón, Quintero Javier, Segú-Vergés Cristina, Rodríguez Monterde Pilar, Pozo-Rubio Tamara, Coma Mireia, Montoto Carmen
Unidad Ambulatoria de Psiquiatría y Salud Mental de la Infancia, Niñez y Adolescencia, Hospital Perpetuo Socorro, Badajoz, Spain.
Servicio de Psiquiatría, Hospital Universitario Infanta Leonor, Universidad Complutense, Madrid, Spain.
Front Psychiatry. 2023 Jun 2;14:939650. doi: 10.3389/fpsyt.2023.939650. eCollection 2023.
Attention-deficit/hyperactivity disorder (ADHD) is an impairing psychiatric condition with the stimulants, lisdexamfetamine (LDX), and methylphenidate (MPH), as the first lines pharmacological treatment.
Herein, we applied a novel method to evaluate virtual LDX (vLDX) and vMPH as treatments for ADHD applying quantitative systems pharmacology (QSP) models. The objectives were to evaluate the model's output, considering the model characteristics and the information used to build them, to compare both virtual drugs' efficacy mechanisms, and to assess how demographic (age, body mass index, and sex) and clinical characteristics may affect vLDX's and vMPH's relative efficacies.
We molecularly characterized the drugs and pathologies based on a bibliographic search, and generated virtual populations of adults and children-adolescents totaling 2,600 individuals. For each virtual patient and virtual drug, we created physiologically based pharmacokinetic and QSP models applying the systems biology-based Therapeutic Performance Mapping System technology. The resulting models' predicted protein activity indicated that both virtual drugs modulated ADHD through similar mechanisms, albeit with some differences. vMPH induced several general synaptic, neurotransmitter, and nerve impulse-related processes, whereas vLDX seemed to modulate neural processes more specific to ADHD, such as GABAergic inhibitory synapses and regulation of the reward system. While both drugs' models were linked to an effect over neuroinflammation and altered neural viability, vLDX had a significant impact on neurotransmitter imbalance and vMPH on circadian system deregulation. Among demographic characteristics, age and body mass index affected the efficacy of both virtual treatments, although the effect was more marked for vLDX. Regarding comorbidities, only depression negatively impacted both virtual drugs' efficacy mechanisms and, while that of vLDX were more affected by the co-treatment of tic disorders, the efficacy mechanisms of vMPH were disturbed by wide-spectrum psychiatric drugs. Our results suggested that both drugs could have similar efficacy mechanisms as ADHD treatment in adult and pediatric populations and allowed raising hypotheses for their differential impact in specific patient groups, although these results require prospective validation for clinical translatability.
注意力缺陷多动障碍（ADHD）是一种具有损害性的精神疾病，兴奋剂赖右苯丙胺（LDX）和哌甲酯（MPH）是一线药物治疗手段。
在此，我们应用一种新方法，运用定量系统药理学（QSP）模型评估虚拟LDX（vLDX）和vMPH作为ADHD治疗药物的效果。目标是考虑模型特征及用于构建模型的信息来评估模型输出，比较两种虚拟药物的疗效机制，并评估人口统计学特征（年龄、体重指数和性别）及临床特征如何影响vLDX和vMPH的相对疗效。
我们基于文献检索对药物和病症进行分子特征分析，并生成了总计2600名成人及儿童 - 青少年的虚拟人群。对于每个虚拟患者和虚拟药物，我们运用基于系统生物学的治疗性能映射系统技术创建了基于生理的药代动力学和QSP模型。所得模型预测的蛋白质活性表明，两种虚拟药物通过相似机制调节ADHD，尽管存在一些差异。vMPH诱导了几个一般的突触、神经递质和神经冲动相关过程，而vLDX似乎更特异性地调节与ADHD相关的神经过程，如GABA能抑制性突触和奖励系统的调节。虽然两种药物的模型都与对神经炎症的影响和神经活力改变有关，但vLDX对神经递质失衡有显著影响，而vMPH对昼夜节律系统失调有影响。在人口统计学特征中，年龄和体重指数影响两种虚拟治疗的疗效，尽管对vLDX的影响更为明显。关于合并症，只有抑郁症对两种虚拟药物的疗效机制产生负面影响，虽然vLDX的疗效机制在合并抽动障碍时受影响更大，但vMPH的疗效机制受到广谱精神药物的干扰。我们的结果表明，两种药物在成人和儿童人群中作为ADHD治疗药物可能具有相似的疗效机制，并为它们在特定患者群体中的差异影响提出了假设，尽管这些结果需要前瞻性验证以实现临床转化。
