Treatment With Antipsychotics in Pregnancy: Changes in Drug Disposition

Abstract

Although pregnancy is known to cause changes in drug pharmacokinetics, little is known about its impact on serum levels of antipsychotics. In this study we retrospectively assessed 201 routine serum antipsychotic therapeutic drug monitoring concentration measurements obtained from a total of 110 pregnancies in 103 women, and 512 measurements from the same women before and after pregnancy. Serum concentrations in the third trimester were significantly lower than baseline for quetiapine (-76%; confidence interval (CI), -83%, -66%; P < 0.001) and aripiprazole (-52%; CI, -62%, -39%; P < 0.001), but not for olanzapine (-9%; CI, -28%, +14%; P = 0.40). For the remaining antipsychotics (perphenazine, haloperidol, ziprasidone, risperidone, and clozapine), our dataset was limited, but it indicates that concentrations may decline at least for perphenazine and possibly also for haloperidol. Even though the clinical consequence of the serum concentrations decline remains to be elucidated, our results warrant close clinical monitoring throughout pregnancy, preferentially supported by therapeutic drug monitoring.

Figure 1

Flow of sample identification and inclusion of therapeutic drug monitoring samples of antipsychotic drugs obtained during pregnancy. ^aSix measurements were excluded due to the following drug interactions: clozapine + fluvoxamine (n = 1), olanzapine + carbamazepine (n = 1), perphenazine + paroxetine (n = 2), perphenazine + fluoxetine (n = 1), and risperidone + fluoxetine (n = 1). [Color figure can be viewed at cpt-journal.com]

Figure 2

Quetiapine, olanzapine, and aripiprazole serum concentrations in pregnancy. The figures to the left show each of the observed serum concentrations of the study, adjusted to the doses presented in the figure headings. Measurements from the same women in a nonpregnant 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 t weeks after delivery would be shown t weeks to the right of the vertical dashed line. For aripiprazole the concentrations shown represent the active moiety (parent drug + metabolite). Six outliers for quetiapine are not shown in the figure. These were four measurements at week 0 (concentrations of 554, 536, 470, 440 ng/mL), one measurement at week 7 (302 ng/mL), and one measurement at week D+3 (315 ng/mL). The horizontal lines represent the median (dark gray), 25‐ and 75‐percentiles (light gray), and 10‐ and 90‐percentiles (white) for concentration measurements (adjusted to the doses presented in the figure headings) for all women aged 18–45 years from the St Olav University Hospital TDM database. The figures to the right show the expected serum concentrations across pregnancy for women using the antipsychotic doses presented in the figure headings. The regression lines are shown with solid lines, and the 95% confidence limits with dashed lines. For aripiprazole the concentrations shown represent the active moiety (parent drug + metabolite). D+12 = Delivery + 12 weeks. [Color figure can be viewed at cpt-journal.com]