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 N-desmethylfluoxetine, 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 half-lives 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, O-demethylation 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.