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Disposition of Chiral and Racemic Fluoxetine and Norfluoxetine Across Childbearing

Sit, Dorothy MD; Perel, James M. PhD; Luther, James F. MA; Wisniewski, Stephen R. PhD; Helsel, Joseph C. BS; Wisner, Katherine L. MD, MS

Journal of Clinical Psychopharmacology:
doi: 10.1097/JCP.0b013e3181e7be23
Original Contributions
Abstract

Objective: To add to the limited data on the clinical pharmacology of antidepressants during pregnancy, we examined the dose-corrected chiral and racemic levels (level/dose) of fluoxetine (FLX) and norfluoxetine (NorFLX) during pregnancy and early postpartum.

Methods: The authors evaluated 17 pregnant women who received fluoxetine therapy. Doses were recorded weekly across gestation and postpartum. At 20, 30, and 36 weeks of gestation, during delivery, and 12 weeks after delivery, the depression level was assessed with the Hamilton Rating Scale for Depression (HRS-D), and plasma samples were analyzed for levels of S- and R-FLX and S- and R-NorFLX.

Results: The mean ratios of the chiral parent drug (S-FLX + R-FLX) to metabolite levels (S-NorFLX + R-NorFLX) decreased across pregnancy. The differences were significant between 20-36 weeks and 30-36 weeks. After delivery, the mean dose-corrected level of the active moiety S-FLX and the mean ratio of the chiral parent drug (S-FLX + R-FLX) to metabolite level (S-NorFLX + R-NorFLX) significantly increased between delivery and 12 weeks postpartum. Most of the fluoxetine-treated subjects experienced remitted depressive episodes and euthymic mood levels during pregnancy and postpartum.

Conclusions: The findings extend earlier reports of increased antidepressant metabolism during pregnancy and refractory metabolism after delivery. These data may inform treatment decisions related to dosing in patients who receive fluoxetine during pregnancy.

Author Information

From the Women's Behavioral HealthCARE, Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA.

Received October 19, 2009; accepted after revision May 13, 2010.

Reprints: Dorothy Sit, MD, Women's Behavioral HealthCARE, Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, 3811 O'Hara St, Oxford 410, Pittsburgh, PA 15213 (e-mail: sitdk@upmc.edu).

Dr Sit's contributions were supported by the National Institute of Mental Health (NIMH) grant R01 MH60335 (K Wisner, PI), the Junior Faculty Scholar's Program NIMH R25 MH060473 (P Pilkonis, PI), and the Career Development Award NIMH 1K23 MH082114 (D Sit, PI).

Dr Wisniewski receives grant supports from the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Neurological Disorders and Stroke, and the National Institute of Mental Health, Bethesda, MD.

Dr Wisner's effort was supported primarily by the NIMH grants R01 MH60335 (Antidepressant Drug Use During Pregnancy), R01 MH071825 (Identification and Therapy of Postpartum Depression), R01 MH075921 (Antimanic Use During Pregnancy), and R01 MH057102 (Transdermal Estradiol for Postpartum Depression).

The data were presented at the 47th NCDEU Annual Meeting, Boca Raton, June 2007; 31st Annual Meeting of the Teratology Society, Pittsburgh, June 2007; International Marce Society, Sydney, September 2008; and the 11th International Congress of Therapeutic Drug Monitoring and Clinical Toxicology, Montreal, October 2009.

The trial is registered at http://www.clinicaltrials.gov; NCT00279370.

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© 2010 Lippincott Williams & Wilkins, Inc.