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OPTIMIZING MEDICATION MANAGEMENT FOR MOTHERS WITH DEPRESSION
Katherine L. Wisner, MD, MS, Northwestern University, Chicago, IL
During pregnancy, the activities of Cytochrome (CYP) P450 enzymes are altered.
However, minimal information is available to inform dosing guidelines. My team has
published data demonstrating that the plasma concentrations of sertraline, fluoxetine,
citalopram and escitalopram decline across pregnancy.
Sertraline is produced as the S-isomeric compound and is extensively metabolized by
the following CYP450 enzymes: major pathway, 2B6; minor pathways, 2C9, 2C19, 2D6,
3A4/5. We examined dose requirements and plasma concentration-to-dose (C/D) ratios
in six women at 20, 30, 36 weeks, delivery, and 2, 4-6 weeks and 3 months after birth.
The mean C/D ratios for sertraline decreased by an average of 60% between 20 weeks
and delivery, which reflects elevated drug metabolism. By 4-6 weeks postpartum, C/D
ratios of sertraline were similar to those in early pregnancy.
Although CYP2D6 is the primary enzyme that metabolizes fluoxetine (FLX) to Ndesmethylfluoxetine, 3A4 and 2C9 play a moderate role and 1A2, 2B6, 2C8 and 2C19 also
contribute. In 17 pregnant women treated with FLX, we observed that the C/D ratios
declined in the third trimester, and a significant negative relationship between
depression scores and FLX was observed.
Citalopram (CIT) is a racemic mixture of S- and R-CIT, with only the S-enantiomer
having biological activity. Two compounds are marketed as antidepressants (CIT =Celexa,
and esCIT=Lexapro). Both enantiomers of CIT are initially metabolized by CYP2C19 and
CYP3A4 and further metabolized by CYP2D6. We studied 3 pregnant women treated with
CIT and 2 treated with esCIT. In 4 of 5 subjects, the C/D ratios for the stereoisomers of
the parent compound and primary metabolite decreased between 20 weeks gestation
and delivery. By 12 weeks postpartum the C/D ratios were similar to those at 20 weeks
gestation.
These limited studies illustrate that the mean C/D ratios for sertraline, FLX, and
CIT/esCIT decrease in the second half and specifically in the third trimester, presumably
due to increased hepatic metabolism. However, the impact of these changes on
depressive symptom relapse, and, in response, dose escalation has not been elucidated.
My team was awarded funding from the National Institute of Child Health and Human
Development to study the disposition of these drugs in 200 women. Due to the long halflives of the SSRIs, it was impractical to conduct formal pharmacokinetic studies because
doses would need to be withheld for several days, which risks increased depressive and
discontinuation symptoms.
We will measure serial trough plasma concentrations, with women acting as their own
controls across pregnancy. Plasma SSRI parent drug and metabolite concentrations will
be measured as well as plasma concentration to dose (C/D) ratios of the parent drug and
metabolite-to-parent drug concentration ratios. The effect of changing maternal SSRI
concentrations on disease expression will be determined by assessing depressive
symptoms and side effects monthly and before dose changes. We will repeat these
assessments twice postpartum as non-pregnant physiology is re-established.
Probe studies will be conducted in the third trimester and after birth to assess the
relative contributions of CYP 450 enzymes as they act in concert to metabolize these
drugs. The probe medications and their metabolic pathways are: dextromethorphan, Odemethylation by CYP2D6; omeprazole, 5-hydroxylation by CYP2C19; midazolam, 1’hydroxylation by CYP3A4; and tolbutamide 4-hydroxylation by CYP2C9.
We also will investigate the effect of genomic variability on inter-individual differences
in SSRI plasma concentrations. At study entry, subjects will be categorized as ultrarapid,
extensive, intermediate, or poor metabolizers. Those taking fluoxetine will be classified
based on CYP2D6 genotypes, citalopram and escitalopram on CYP2C19, and sertraline on
CYP2C19. Primary outcomes of interest include: C/D ratios for each drug; and depression
and side effects scores. These data will inform guidelines for optimal dosing of these
SSRIs.
What will the audience take away from your presentation? The audience will learn:
 The changes in CYP enzyme systems that metabolize antidepressants during
pregnancy and how they affect drug plasma concentrations.
 Strategies for monitoring women during pregnancy for symptom recurrence and
when recurrences are most likely to occur.
 From cCase examples of dose management of pregnant women.
 The management of antidepressant dosing as the woman transitions from pregnant
to postpartum physiology.
This abstract is not connected to an organized session.
Biography
Katherine L. Wisner M.D., M.S., is the Norman and Helen Asher Professor of Psychiatry
and Obstetrics and Gynecology and Director, Asher Center for the Study and Treatment of
Depressive Disorders, Northwestern University in Chicago, Illinois. She is internationally
recognized as an expert in the treatment of mood disorders during pregnancy and the
postpartum period. She is a fellow in the American College of Neuropsychopharmacology
and has authored 210 peer-reviewed articles and 18 book chapters. She received the
Woman in Science Award from the American Medical Women’s Association, the Alexandra
Symonds Award from the American Psychiatric Association and the Marcè International
Society for Perinatal Mental Health’s Medal for lifetime contributions.
Author Details:
Full Name: Katherine L. Wisner, MD, MS
Contact Number: 312 695 8441
Country: United States
Category: Oral Presentation
Session Name: n/a
Email: [email protected]