A STUDY TO EVALUATE EFFECTS OF ESCITALOPRAM AND CITALOPRAM ON PK OF DESIPRAMINE

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 目的：许多常用的抗抑郁药对细胞色素P450系统均有不同程度的抑制作用。 外消旋混合物西酞普兰表现出对CYP 2D6的适度抑制活性，正如我们在先前研究中的工作所证明的那样。 外消旋艾司西酞普兰与西酞普兰对该同工酶的影响尚未进行直接比较。 本研究的目的是利用地昔帕明AUC的变化作为酶活性的指标，确定艾司西酞普兰与西酞普兰对CYP2D6的抑制潜力。 此外，我们还将利用心电图描记和简易精神状态检查（MMSE）评分比较两种药物之间地昔帕明的药效学变化。 还将获得一氧化氮（NOx）的代谢终产物，以评估这些抗抑郁药对NO产生的影响。 帕罗西汀（一种对CYP2D6具有强效抑制作用的SSRI）给药后，NOx平均值显著增加。 一氧化氮已被认为是一种介体，降低了神经元活动。 研究报告：将通过传单从VA和UTHSCSA校园招募正常健康受试者参与随机交叉设计研究。 患者将在GCRC接受筛选、基线评估和研究评估。 方法：将招募6名受试者。 筛选后，受试者将接受基线评估，包括地昔帕明AUC、NOx、地昔帕明给药后T0和T2小时的ECG描记以及给药后T0和T2小时的MMSE。 受试者还将使用美沙芬进行CYP2D6活性评估，并在给药后4小时采集尿液。 然后，受试者将随机接受chialopram（滴定至每日40 mg）或艾司西酞普兰（滴定至每日10 mg），共14天。 将在第8天重复地昔帕明AUC、NOx、ECG描记、MMSE和美沙芬激发。 然后受试者将经历一个灵活的洗脱期，然后开始第二种抗抑郁药（地酞普兰或艾司西酞普兰）并重复相同的程序。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. OBJECTIVE: Many commonly used antidepressants have varying degrees of inhibitory action on the cytochrome P450 system. The racemic mixture citalopram demonstrates modest inhibitory activity at CYP2D6, as demonstrated by our work in a previous study. The racemate escitalopram has not been directly compared with citalopram in regard to its effects on this isoenzyme. The objective of this study is to determine the inhibitory potential of escitalopram versus citalopram on CYP2D6, utilizing changes in desipramine AUC as an indicator of enzyme activity. Additionally, we will compare the pharmacodynamic changes in desipramine between the two agents utilizing ECG tracings and Mini-Mental Status Exam (MMSE) scores. Metabolic end-products of nitric oxide (NOx) will also be obtained to assess the effects of these antidepressants on NO production. Administration of paroxetine, an SSRI with potent inhibitory effects on CYP2D6, has demonstrated significant mean increase in NOx. Nitric oxide has been implicated as a mediator of decreased CYP activity. RESEARCH PLAN: Normal healthy subjects will be recruited from a VA and UTHSCSA campus via flyer to participate in the randomized, crossover design study. Patients will undergo screening, baseline assessments, and research assessments at the GCRC. METHODS: Six subjects will be recruited. After screening, subjects will undergo a baseline assessment, including desipramine AUC, NOx, ECG tracings at T0 and T2 hours post desipramine administration, and MMSE at T0 and T2 hours post. Subjects will also undergo CYP2D6 activity assessment using dextromethorphan and 4 hour post-administration urine collection. Subjects will then be randomized to receive chialopram, titrated to 40 mg daily, or escitalopram, titrated to 10 mg daily, for a total of 14 days. Desipramine AUC, NOx, ECG tracings, MMSE, and dextromethorphan challenge will be repeated on Day 8. Subjects will then undergo a flexible washout period, then begin the second antidepressant (ditalopram or escitalopram) and repeat the same procedures.