Selective serotonin reuptake inhibitors and venlafaxine in pregnancy: Changes in drug disposition

Abstract

BackgroundPregnancy may cause changes in drug disposition. The clinical consequences may be profound and even counterintuitive; in some cases pregnant women may need more than twice their usual drug dose in order to maintain therapeutic drug levels. For antidepressants, evidence on drug disposition in pregnancy is scarce. The aim of this study was to determine the effects of pregnancy on serum levels of selective serotonin reuptake inhibitors (SSRIs) and venlafaxine in a large and naturalistic patient material, in order to provide tentative dose recommendations for pregnant women.MethodsUsing patient data from two routine therapeutic drug monitoring (TDM) services in Norway with linkage to the national birth registry, dose-adjusted serum drug concentrations of SSRIs and venlafaxine during pregnancy were compared to the women’s own baseline (non-pregnant) values, using a linear mixed model.FindingsOverall, the TDM databases contained 196,726 serum concentration measurements from 54,393 women. After data linkage and drug selection (SSRIs or venlafaxine only), we identified 367 analyses obtained from a total of 290 pregnancies in 281 women, and 420 baseline observations from the same women. Serum concentrations in the third trimester were significantly lower than baseline for paroxetine (–51%; 95% confidence interval [CI], –66%, –30%; p<0.001), fluvoxamine (–56%; CI, –75%, –23%; p = 0.004) and citalopram (–24%; CI, –38%, –7%; p = 0,007), and higher than baseline for sertraline (+68%; CI, +37%, +106%; p<0.001). For escitalopram, fluoxetine and venlafaxine concentrations did not change significantly.ConclusionsFor paroxetine and fluvoxamine the pronounced decline in maternal drug serum concentrations in pregnancy may necessitate a dose increase of about 100% during the third trimester in order to maintain stable concentrations. For fluoxetine, venlafaxine, citalopram, escitalopram and sertraline, the present study indicates that dose adjustments are generally not necessary during pregnancy.

Sertraline concentrations in pregnant women are steady and the drug transfer to their infants is low

“…This study on sertraline concentrations in pregnant women and their infants demonstrates an over 10-fold interindividual variability in sertraline and its metabolite plasma concentrations across the course of the pregnancy (Table 2), supporting previous studies from both pregnant and non-pregnant populations [7,12,17]. The intraindividual variability during pregnancy is low, presented in supplemental Fig.…”

“…Sertraline is one of the most commonly used selective serotonin reuptake inhibitors (SSRI) during pregnancy, and generally proven safe for this use [1][2][3][4][5][6]. Plasma sertraline concentrations are shown to both increase and decrease during pregnancy [7][8][9]. No clear association has been found between the dose of sertraline or the plasma sertraline concentration and the clinical effect [10][11][12][13][14][15].…”

“…The importance of CYP2B6, CYP3A4, CYP2C9, and CYP2D6 for the disposition of sertraline in vivo is not yet clear [22,[24][25][26]. Pregnancy induces changes in metabolic enzyme activity, with the activity of CYP2C19 being slightly down-regulated, and the activities of the other potentially important enzymes being upregulated [7][8][9]21]. As the pharmacokinetics change during pregnancy, therapeutic drug monitoring (TDM) might be a way to improve both safety and efficacy of the treatment [7,12,16,17].…”

Skal gravide ha lavere eller høyere legemiddeldoser?

“…Som det fremgår av eksemplene i figur 1 og tabell 1 (2, 9,10,11,12,13,14,15,16) fører endringene i legemiddelkonsentrasjonen hos gravide som regel til at konsentrasjonene faller, vanligvis på grunn av økt levermetabolisme eller økt renal utskilling. Disse endringene kan medføre at dosen som en kvinne «alltid» har brukt før hun ble gravid, blir for lav under svangerskapet.…”

Neonatal Outcomes in Maternal Depression in Relation to Intrauterine Drug Exposure

“…In pregnancy there are changes in drugs absorption, distribution, metabolism, and elimination. Therefore, antidepressants dosage should be increased to maintain a therapeutic effect (13, 14). Fetal exposure to antidepressants occurs through umbilical cord blood flow, placental transport, and absorption from amniotic fluid.…”