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. 2017 Jul 14;12(7):e0181082.
doi: 10.1371/journal.pone.0181082. eCollection 2017.

Selective Serotonin Reuptake Inhibitors and Venlafaxine in Pregnancy: Changes in Drug Disposition

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Selective Serotonin Reuptake Inhibitors and Venlafaxine in Pregnancy: Changes in Drug Disposition

Andreas Austgulen Westin et al. PLoS One. .
Free PMC article

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Background: Pregnancy 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.

Methods: Using 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.

Findings: Overall, 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.

Conclusions: For 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.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.


Fig 1
Fig 1. Inclusion flow chart.
Sample identification and inclusion of therapeutic drug monitoring samples of selective serotonin reuptake inhibitors and venlafaxine obtained during pregnancy.
Fig 2
Fig 2. The serum antidepressant concentrations across pregnancy.
The figure shows each of the observed serum concentrations in the study, adjusted to the doses presented in Table 2. Observations from the same women in non-pregnant state (baseline values) are shown as pregnancy week 0. Delivery is set to pregnancy week 40. Thus, for a woman who gave birth in week 38, a sample drawn x weeks after delivery would be shown x weeks to the right of the vertical delivery line. For fluoxetine and venlafaxine the concentrations shown represent the active moiety (parent drug + metabolite). Three outliers for escitalopram are not shown in the figure. These are one analysis in week 0 (concentration 36 ng/mL), one analysis in week 4 (concentration 36 ng/mL) and one analysis in week 5 (concentration 40 ng/mL). However, these concentrations are included in the statistical analyses. The horizontal lines represent the median (dark grey), 25 and 75 percentiles (light grey) and 10 and 90 percentiles (white) for dose-adjusted serum concentration measurements for all women aged 18–45 years from the St. Olav University Hospital TDM database. For further details, see Methods section.
Fig 3
Fig 3. Regression lines for serum antidepressant concentrations across pregnancy.
The figure shows the expected serum concentrations across pregnancy for women using the antidepressant doses presented in Table 2. The regression lines are shown in blue, and the 95% confidence limits with dashed black lines. For fluoxetine and venlafaxine the concentrations shown represent the active moiety (i.e. parent drug plus metabolite).

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    1. Muzik M, Hamilton SE. Use of antidepressants during pregnancy?: What to consider when weighing treatment with antidepressants against untreated depression. Maternal and child health journal. 2016;20(11):2268–79. doi: 10.1007/s10995-016-2038-5 - DOI - PubMed
    1. Larsen ER, Damkier P, Pedersen LH, Fenger-Gron J, Mikkelsen RL, Nielsen RE, et al. Use of psychotropic drugs during pregnancy and breast-feeding. Acta Psychiatr Scand Suppl. 2015;(445):1–28. doi: 10.1111/acps.12479 - DOI - PubMed
    1. Alwan S, Friedman JM, Chambers C. Safety of selective serotonin reuptake inhibitors in pregnancy: A review of current evidence. CNS drugs. 2016;30(6):499–515. doi: 10.1007/s40263-016-0338-3 - DOI - PubMed
    1. Anderson GD. Pregnancy-induced changes in pharmacokinetics: a mechanistic-based approach. Clin Pharmacokinet. 2005;44(10):989–1008. doi: 10.2165/00003088-200544100-00001 - DOI - PubMed
    1. Costantine MM. Physiologic and pharmacokinetic changes in pregnancy. Front Pharmacol. 2014;5:65 doi: 10.3389/fphar.2014.00065 - DOI - PMC - PubMed

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The authors received no specific funding for this work.