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

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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.