Original Contribution Pharmacokinetics of Sertraline Across Pregnancy and Postpartum Marlene P. Freeman, MD,*y Paul E. Nolan Jr, PharmD,z Melinda F. Davis, PhD,x Marietta Anthony, PhD,k Karen Fried, BA,z Martha Fankhauser, MS Pharm,z Raymond L. Woosley, MD ,PhD,k and Francisco Moreno, MDy Abstract: Insufficient data inform dosing of antidepressants and clinical monitoring for Major Depressive Disorder (MDD) during the perinatal period. The objectives were to assess the pharmacokinetics of sertraline (SER) across pregnancy and postpartum. Participants treated with SER for MDD underwent serial sampling to measure steady-state concentrations of SER and norsertraline during the second and third trimesters and postpartum (total of 3 assessments). Blood was drawn before observed SER administration and 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours after administration. A sensitive high-performance liquid chromatography/mass spectrometric method for simultaneous determination of serum concentrations of SER and norsertraline was developed and validated. For each sampling period for SER, area under the serum concentration versus time curve, maximal serum concentration (Cmax), and the time at which Cmax occurred (Tmax) were determined. Of 11 women initially enrolled, 6 completed second- and third-trimester assessments, and 3 completed all 3 assessments (including the postpartum assessment). Mean changes on all pharmacokinetic parameters were nonsignificant between assessments, although there was a marked heterogeneity among individuals. Results were not significantly altered by incorporation of body weights into the analyses. The range of pharmacokinetic changes between individuals was broad, indicating heterogeneity regarding the impact of pregnancy on SER metabolism. Overall, lowest observed SER area under the curve and Cmax occurred in the third trimester (observed in 5 of 6 participants). Despite nonsignificant mean pharmacokinetic changes, the range of pharmacokinetic changes across pregnancy warrants careful monitoring of depressive symptoms in women with MDD in late pregnancy and further study. *Departments of Psychiatry and Obstetrics and Gynecology, Women’s Mental Health Center, University of Texas Southwestern Medical Center at Dallas, Dallas, TX; and yDepartment of Psychiatry, University of Arizona College of Medicine; zDepartment of Pharmacy Practice and Science, University of Arizona College of Pharmacy; xDepartment of Pediatrics, University of Arizona College of Medicine; and kThe Critical Path Institute, Tucson, AZ. Received January 26, 2008; accepted after revision August 25, 2008. This study was funded by the US Food and Drug Administration Office of Women’s Health 223-03-8723, task order no. 1, and the National Institute of Mental Health K23 MH66265 (for the principal investigator’s time). Address correspondence and reprint requests to Marlene P. Freeman, MD, Department of Psychiatry, Massachusetts General Hospital, Simches Research Building, Floor 2, 185 Cambridge St, Boston, MA 02114, 617-724-8020. E-mail: [email protected]. Copyright * 2008 by Lippincott Williams & Wilkins ISSN: 0271-0749/08/2806-0646 DOI: 10.1097/JCP.0b013e31818d2048 646 (J Clin Psychopharmacol 2008;28:646–653) M ajor depressive disorder (MDD) is common during pregnancy and postpartum, and antidepressants are often used during these periods.1–4 The assessment of the risks and benefits of antidepressants during pregnancy are complicated, and a growing body of literature supports the need to carefully consider both the risks of untreated MDD and antidepressant medication exposure.5–7 Once a decision is made to commence or continue an antidepressant during pregnancy, there is a paucity of data to inform appropriate dosing and clinical monitoring. Factors that may impact pharmacokinetics during pregnancy include increased plasma volume, total body water, and extracellular fluid space; decreased concentration of plasma albumin; increased regional blood flow changes; changes in hepatic metabolism of some drugs; and gastrointestinal changes.8,9 Some medications are well known to require monitoring and frequent dose adjustments to maintain therapeutic benefit during pregnancy. For example, pregnant women treated with lithium or lamotrigine may require increased doses late in pregnancy to maintain therapeutic drug blood levels and clinical benefits.10 It is unclear what dose changes or monitoring, if any, are required with antidepressants. A limited amount of data have been published in the area of antidepressant dosing requirements throughout pregnancy. Most studies suggest a possible need for higher dosing in late pregnancy, although the studies have generally been limited by small numbers of subjects and single blood draws after the subject has taken the antidepressant. In 1 study by Wisner et al,11 pregnant women (N = 8) with histories of good response to tricyclic antidepressants were followed up, and doses were adjusted based on clinical need. Serum samples were collected 12 to 18 hours after drug administration after the dose was stable for at least 1 week. The investigators observed that dosing requirements during the third trimester ranged from 1.3 to 2 times the dose that the patients required when they were not pregnant. Serum levels substantiated that higher dosing in late pregnancy was required to maintain therapeutic levels. Dose requirements escalated in the third trimester from earlier in pregnancy. Similarly, Altshuler and Hendrick12 reported 2 cases in which tricyclic antidepressant blood levels were lower in the second half of pregnancy and Journal of Clinical Psychopharmacology Volume 28, Number 6, December 2008 Copyright @ 2008 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Journal of Clinical Psychopharmacology Volume 28, Number 6, December 2008 correlated with increased need for higher doses clinically for the treatment of MDD. Klier et al13 reported a case (N = 1) in which values of venlafaxine and quetiapine area under the curve (AUC) were reduced in a pregnant patient as compared with her AUC values postpartum. In the case of selective serotonin reuptake inhibitor (SSRI) use in pregnancy, a limited amount of data suggests that escalating doses may be required to maintain efficacy as the pregnancy progresses.14 In 1 study, fluoxetine (in typically prescribed dosage ranges) was demonstrated to result in relatively low serum levels during pregnancy, likely because of a more rapid metabolism of the drug.15 The rate of metabolism of fluoxetine to norfluoxetine, its major metabolite, was 2.4-fold higher in late pregnancy than at 2 months postpartum. Sit et al16 assessed pharmacokinetics and dosing requirements across pregnancy and during the postpartum in 3 women who were treated with citalopram, 2 treated with escitalopram, and 6 treated with sertraline (SER). Blood samples were collected 8 to 15 hours postdose. The investigators found that dose requirements were higher in late pregnancy as compared with earlier in gestation and postpartum. We sought to determine the pharmacokinetics of SER across pregnancy with a rigorous approach using serial blood levels after observed dosage administration in the second trimester, third trimester, and postpartum. In this study, we elected to monitor women who were receiving treatment with SER, which was selected based on wide utilization, data demonstrating low levels of exposure via breast milk to breastfed infants, and lack of adverse events in breast-feeding infants.17–21 Maternal SER use was previously observed to produce the lowest ratios of cord blood concentrations to maternal serum relative to other SSRIs.22 At the time the protocol was developed, SER (brand Zoloft) was the most prescribed antidepressant in the United States. METHODS Subjects We used a longitudinal design, allowing for women to serve as their own controls during the postpartum year, as recommended by the US Food and Drug Administration (FDA) for pharmacokinetic studies in pregnant women. (Guidance for Industry Pharmacokinetics in Pregnancy—Study Design, Data Analysis, and Impact on Dosing and Labeling [2004]; Office of Training and Communications; Division of Drug Information, HFD-240; Center for Drug Evaluation and Research; Food and Drug Administration; 5600 Fishers Lane; Rockville, MD 20857; available at: http://www.fda.gov/cder/guidance/ 5917dft.htm). Pregnant women who were currently receiving treatment with SER, aged 18 to 45 years, were recruited in their first or second trimester of pregnancy. Women were eligible if they were currently taking SER (at least 2 weeks on a stable daily dose), able to provide written informed consent, and had a history of MDD, as defined by Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria, verified using the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (SCID). SER Pharmacokinetics—Pregnancy/Postpartum Exclusion criteria were as follows: current active suicidal or homicidal ideation; active substance abuse as per history at intake; concurrent medication that would require continuation during the 2 weeks preceding each assessment in the General Clinical Research Center (GCRC), with the exception of thyroid hormone medications, prenatal vitamins, and iron supplements; and Bhigh-risk[ pregnancy as defined by the subject’s obstetrical provider, excluding uncomplicated Badvanced maternal age.[ Referrals were made to the study by health care providers. Initial target enrollment was 20. Protocol The study was approved by the institutional review board at the University of Arizona and the Research Involving Human Subjects Committee of the US FDA. Subjects provided written and verbal consent for participation. The study was implemented through the Women’s Mental Health Program, a specialty clinic within the Department of Psychiatry, and the GCRC at the University of Arizona College of Medicine. Participants came to the GCRC for serial blood sampling to measure SER and its major metabolite, norsertraline (NOR), at steady-state concentrations at multiple time points after dosing (at least 14 days on a constant dose) for up to 3 visits during the pregnancy and postpartum periods: (1) second trimester 22 to 26 weeks’ gestation, (2) third trimester: 30 to 34 weeks’ gestation, and (3) postpartum: 12 to 52 weeks postpartum. Blood samples were obtained according to the following schedule: 0 hours (before the dose of SER) and at 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours after observed administration of SER. To assess the nonpregnant state pharmacokinetics, the third GCRC visit occurred to assess maternal SER and NOR levels between 12 and 52 weeks postpartum after the mother had ceased breast-feeding. Postpartum women therefore served as their own controls for the nonpregnant state to allow for comparison with results generated during their pregnancies. For the safety of the subjects, we obtained a complete blood count before each GCRC visit. Contraindications for blood draws were as follows: hemoglobin level of less than 8 g/dL; baseline heart rate greater than 120 beats/min; orthostatic symptoms; and orthostatic changes on vital signs. If any of these were present on the day of a scheduled GCRC visit, the visit was rescheduled to ensure patient safety. For each GCRC visit, participants fasted for at least 2 hours before the time of observed SER administration. Participants received their usual oral dose of SER with 200 mL of water in the GCRC, and they were allowed to receive food and drink beginning 2 hours after drug administration. Participants refrained from caffeine-containing beverages for at least 4 hours after SER administration. Participants were asked to avoid consumption of grapefruit juice at least 1 full week before and during each GCRC visit because of possible inhibition of the cytochrome P450 (CYP) 3A/4 isoenzymes, which can alter SER metabolism (ie, increase SER concentrations).23 After placement of a peripheral venous catheter, the patency of which was maintained via hourly injections of normal saline, blood samples (approximately 8 mL each) were * 2008 Lippincott Williams & Wilkins Copyright @ 2008 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 647 Journal of Clinical Psychopharmacology Volume 28, Number 6, December 2008 Freeman et al TABLE 1. SER Doses, Body Weights, and Depression Status SER Daily Dose, mg Weight, kg 2nd Trimester 3rd Trimester Postpartum 2nd Trimester 3rd Trimester Postpartum Met Criteria for MDD at Intake Ms A 100 150 150 92.8 93.7 87.8 Yes Ms B 50 50 50 66.2 71.7 55.9 No Ms C 100 100 NA 94.2 99.8 n/a No Ms D 50 100 200 133.9 135.8 137.5 Yes Ms E 50 50 NA 62.0 70.6 NA No Ms F 150 150 NA 74.6 78.0 NA No Ms G Ms H 200 25 NA NA NA NA 79.2 64.8 NA NA NA NA No No NA indicates not available. collected into serum tubes immediately (0 hours) before the patient’s usual daily dose of SER was administered and then at fixed times after dosing. Blood was drawn at the following sample times: predose (time 0) and 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours after dosing. Serum samples were kept frozen at j20-C until analyzed. Laboratory measures were obtained at B0 hours[ for serum albumin and protein, as SER is highly protein bound; liver function tests were also obtained, as SER undergoes extensive hepatic metabolism. A sensitive high-performance liquid chromatography method for the simultaneous determination of serum concentrations of SER and its major metabolite NOR was developed and validated in the Bioanalytical Core Lab of the University of Arizona Health Science Center. The separations were achieved on a silica column with a polar organic mobile phase consisting of acetonitrile and methanol at a flow rate of 0.5 mL/min. The concentrations were measured using mass spectroscopy detection. Because a suitable internal standard was not found, none was used. Sample preparation consisted of a simple liquid-liquid procedure. Briefly, 200 HL of patient serum or spiked drug- free serum for calibration standards was made alkaline by the addition of 1 mol/L sodium hydroxide. Sertraline and NOR were extracted into a mixture of diethyl ether–hexane, 80:20 (vol/vol), by vortex mixing. The ether extracts were evaporated to dryness before they were reconstituted into 200 HL of 0.5% acetic acid in acetonitrile (vol/vol) and transferred into a 200-HL polypropylene autosampler vial. For analysis, an 80-HL aliquot of the reconstituted extract was introduced onto the Agilent 1100 liquid chromatography/mass spectroscopy detection chromatographic system consisting of the following modules: a vacuum degasser, a binary pump, an autosampler, a thermostated column compartment, and a mass selective detector supplied with atmospheric pressure ionization electrospray. The detector was set in selective ion mode for each compound of interest, 306 m/z for SER and 275 m/z for its desmethyl metabolite NOR. Calibration curves, where y represents the peak area of SER or NOR calibration standards in nanograms per milliliter, were generated by least squares linear regression. Both curves were linear through their full range, 5 through 160 ng/mL for SER and 10 through 320 ng/mL for NOR, with TABLE 2. Pharmacokinetic Parameters of SER Across the Perinatal Period: Dose Normalized Ms A Ms B Ms C Ms D Ms E Ms F Ms G Ms H 2nd Trimester 0.43 0.62 0.41 0.63 1.33 0.89 0.37 0.53 3rd Trimester 0.60 0.51 0.32 0.54 1.21 0.77 NA NA Postpartum 0.37 0.77 NA 1.25 NA NA NA 2nd Trimester 4.91 8.33 4.03 9.80 20.30 14.69 5.16 9.06 3rd Trimester 8.20 7.25 2.80 8.17 17.23 12.79 NA NA 6.16 11.38 NA 22.98 NA NA NA NA 2nd Trimester 5.88 20.50 10.98 21.76 74.96 24.81 11.23 28.80 3rd Trimester 10.73 36.55 8.10 17.01 70.85 36.38 NA NA 6.40 36.80 NA 46.59 NA NA NA NA Cmax, ng/mL per mg SER AUC (0–24 h), (ng/mL) h per mg Postpartum NOR AUC (0–24 h), (ng/mL) h per mg Postpartum All SER values were dose normalized. NA indicates not available. 648 * 2008 Lippincott Williams & Wilkins Copyright @ 2008 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Journal of Clinical Psychopharmacology Volume 28, Number 6, December 2008 SER Pharmacokinetics—Pregnancy/Postpartum TABLE 3. Pharmacokinetic Parameters of SER Across the Perinatal Period (Not Dose Normalized) Ms A Ms B Ms C Ms D Ms E Ms F Ms G Ms H SER Cmax, ng/mL 2nd Trimester 42.6 31.1 40.5 31.6 66.4 133.2 73.4 13.2 3rd Trimester Postpartum 89.7 55.4 25.6 38.5 31.5 NA 53.7 249.8 60.6 NA 115.5 NA NA NA NA NA SER AUC (0–24 h), (ng/mL) h 2nd Trimester 490.61 416.27 402.74 489.77 1014.80 2202.99 1032.63 226.48 3rd Trimester 1230.31 362.40 279.70 816.51 333.00 1918.89 NA NA 923.57 569.01 NA 4596.08 NA NA NA NA Postpartum NOR AUC (0–24 h), (ng/mL) h 2nd Trimester 588.28 1025.16 1097.79 1087.93 3747.88 3721.79 2245.22 226.48 3rd Trimester Postpartum 1609.75 959.32 1827.57 1840.13 810.32 NA 1700.92 9318.89 3542.25 NA 5457.21 NA NA NA NA NA NA indicates not available. correlation coefficients of r2 Q 0.99. Quality control standards at 3 levels, low (8/16 ng/mL, SER/NOR), medium (32/64 ng/mL, SER/NOR), and high (128/256 ng/mL, SER/ NOR), were run in replicates for interday and intraday variability; for intraday, the percent coefficient of variation was 7.3 or less (n = 5) for both SER and NOR, whereas the value of percent coefficient of variation for interday variability was 12.7 or less (n = 15) for both SER and NOR. A standard curve and a set of quality control standards, in triplicate, were analyzed along with each batch of patient samples. For each sampling period for SER, area under the serum concentration versus time curve (AUC), maximal serum concentration (Cmax), and the time at which Cmax occurred (Tmax) were determined using the noncompartmental pharmacokinetic model provided by WinNonlin version 5.1 (Pharsight Corporation, Mountain View, Calif). For NOR, AUC and the NOR/SER AUC ratios were also calculated. Sertraline AUC, Cmax, and NOR AUC were dose normalized (ie, values divided by the patient’s dose at the time of sampling), because of varying doses within and between subjects. Dose normalizing was required, because dose changes made by prescribing physicians outside the study as part of clinical treatment were common. At each visit, the following were completed: Structured Interview Guide for the Hamilton Depression Rating Scale— Seasonal Affective Disorder version, which incorporates the well-validated and highly used 21-item Hamilton Rating Scale for Depression as well as a set of questions designed to assess atypical symptoms of depression; Edinburgh Postnatal Depression Scale, a 10-item, patient-completed rating scale of depressive symptoms that is frequently used in the obstetric population; the Zung Self-Rating Anxiety Scale; and Clinical Global Impression Scale.24–27 Paired-samples t tests were used to compare SER AUC between the second and third trimesters. Paired-samples t tests were used to compare normalized and nonnormalized results. Normalized and nonnormalized SER AUCs were compared between the second and third trimesters using paired-samples t tests. Nonparametric analyses were also performed in case the underlying population distributions were not normal. RESULTS Subjects Eleven patients were enrolled into the study, of which 8 completed 1 GCRC visit (the second-trimester assessment), 6 completed 2 GCRC visits (second- and third-trimester assessments), and 3 completed all 3 GCRC visits (the 2 pregnancy and postpartum assessments). All of the participants who completed at least 1 GCRC visit (n = 8) were white and non-Hispanic. One Hispanic subject discontinued because of ineligibility of highrisk pregnancy, after her obstetrician determined by ultrasound that she was carrying twins, and 1 fetus was found by ultrasound to have hydrocephalus. The other women who did not complete the study were all white and had normal singleton pregnancies without medical complications. FIGURE 1. SER AUC dose normalized. * 2008 Lippincott Williams & Wilkins Copyright @ 2008 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 649 Journal of Clinical Psychopharmacology Volume 28, Number 6, December 2008 Freeman et al T1 FIGURE 2. SER Cmax dose normalized. FIGURE 4. Serum SER and NOR levels by trimester for Ms A. Because the objective of the study was to determine pharmacokinetic changes across pregnancy and postpartum, and because patients served as their own controls, we focused our results on those who completed at least 2 of the scheduled GCRC visits (n = 6). Of the eight subjects who completed at least 1 GCRC visit, 2 met the criteria for a major depressive episode at enrollment. These 2 subjects were among the 3 to complete all assessments. Three subjects who completed at least 2 GCRC visits required dose increases from the second trimester to the third trimester, based on the clinical judgment of the prescriber and independent of study participation. The women ranged in age from 23 to 36 years, with an average age of 30.5 years (SD, 4.0 years). Seven of the 8 women were married; the eighth was living with her boyfriend. All of the women had at least a high school education, and 4 had a bachelor’s degree or higher. Half of the women were employed or attending school full time. The 3 women with children were either full-time homemakers or worked part time. Two women met the criteria for current MDD at intake, and they were the only women in the study who had more than 1 child (refer to Table 1 for patient SER doses, body weights, and MDD status at baseline [presence or absence of current MDD]). FIGURE 3. NOR/SER ratio. FIGURE 5. Serum SER and NOR levels by trimester for Ms B. 650 Pharmacokinetic Results The pharmacokinetic measures in full are shown in Tables 2 and 3. We used dose-normalized assessment of pharmacokinetic data to account for the dose changes that occurred throughout the trial for individual participants. Dose normalizing was required, because dose changes made by prescribing physicians outside the study as part of clinical treatment were common. Data are presented both with and without normalizing for dose in Tables 2 and 3, and in the accompanying figures. Considerations of the Changes From the Second to the Third Trimester Paired-comparisons t tests were used to examine the changes in SER and NOR AUC from second to third trimester for the 6 women who had 2 clinic visits. The non– dose-adjusted serum concentrations were examined first. Sertraline AUC rose from 836.20 to 911.53 [(ng/mL) h], with an average increase of 75.34 [(ng/mL) h] (SE, 157.28). * 2008 Lippincott Williams & Wilkins Copyright @ 2008 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Journal of Clinical Psychopharmacology Volume 28, Number 6, December 2008 SER Pharmacokinetics—Pregnancy/Postpartum third trimester and postpartum assessments. Dose-normalized SER AUC increased from the third trimester to the postpartum visit by a mean of 4.4% (a statistically nonsignificant change), although only 3 participants completed the postpartum visit. In 2 of 3 participants, the dose-corrected SER AUC and SER Cmax increased postpartum, compared with the third trimester, although mean changes were not statistically significant (Figs. 1–3). Figures 4–6 represent serum SER and NOR (not dose normalized) versus time curves for the 3 participants who completed all pharmacokinetic assessments. Body Weights FIGURE 6. Serum SER and NOR levels by trimester for Ms D. The increase was not significant (t5 = 0.48, P = 0.65). Norsertraline AUC rose from 1878.14 to 2491.34 [(ng/mL) h], with an average increase of 613.20 [(ng/mL) h] (SE, 313.24). This did not reach significance, possibly because of the small sample size (t5 = 1.96, P = 0.11). Two of the women increased their dosage of SER between the second and third trimesters; higher serum concentrations would be expected from the increased dosages alone. To remove the effect of dose changes, we examined dose-normalized serum concentrations. Dose-normalized SER AUC decreased from 10.34 to 9.41 [(ng/mL) h per mg], with an average difference of 0.93 [(ng/mL) h per mg] (SE, 2.19), which was not significant (t5 = j1.05, P = 0.34). Dose-normalized NOR AUC increased from 26.48 to 29.94 [(ng/mL) h per mg]. The average difference was 3.45 [(ng/mL) h per mg] (SE, 8.84), which was also not significant (t5 = 0.96, P = 0.38). Overall, changes from the second- to third-trimester GCRC visits included a mean apparent increase in the oral clearance of SER by 15.7% from the second to the third trimester, as evidenced by decreases in SER AUC during the third trimester. The general pattern of decreased SER AUC (ie, increased SER oral clearance) in the third trimester was observed in 5 of 6 women. However, in 1 case, an individual demonstrated decreased clearance from the second to third trimester (corresponding to increased SER AUC). As regards the SER Cmax, a similar pattern was observed in 5 of 6 women, with SER Cmax tending to decline from the second to third trimester. In the same individual in whom SER AUC increased, Cmax also increased. The ratio of NOR to SER from second to third trimester was highly variable between individuals and across time points, likely reflecting interindividual and intraindividual differences in SER metabolism. The AUC for NOR was also highly variable, among individuals and across trimesters. Postpartum Data Three subjects completed postpartum visits that occurred between 12 and 52 weeks postpartum after cessation of breast-feeding. One patient had a dose increase between the We measured body weights at all GCRC assessments. Body weight increased modestly but significantly as determined by paired t tests from the second to third trimester (P < 0.01). Pharmacokinetic analyses were repeated with the variable of body weight added, and this addition did not significantly alter pharmacokinetic outcomes. Nonparametric analyses were also performed in case the underlying population distributions were not normal. Similar nonsignificant results were obtained. No visits needed to be rescheduled based on laboratory or clinical indications, such as complete blood count or abnormal vital signs. Overall, a broad range was noted, indicating heterogeneity in the influence of pregnancy on the metabolism of SER. DISCUSSION This study adds to the small body of literature on antidepressant pharmacokinetics in pregnancy and postpartum and, in conjunction with other studies, may help to develop strategies for antidepressant dosing and clinical monitoring of MDD during pregnancy and postpartum. We observed a general mean decrease in SER serum levels as pregnancy progressed that was not statistically significant, with lowest dose-adjusted levels observed in the third trimester compared with the second trimester and postpartum for the majority of this small sample. Although the overall mean change in SER AUC during the third trimester was modest, the range of observed changes between patients was large and needs to be considered as potentially clinically relevant for some women. Notable heterogeneity was observed in pharmacokinetics of SER during pregnancy and in the doses prescribed across pregnancy. Intraindividual and interindividual differences in dose requirements are likely impacted by course of illness, metabolic effects of pregnancy, and genetically determined individual differences in metabolism.28–30 Our methods were more rigorous than those of other published studies on this topic, in terms of observed administration of study drug and serial blood level sampling, but our results are consistent with previously published findings. Previous studies have included usually only a single blood draw after medication administration, and medication administration was not reported as observed in previous protocols. Our findings therefore provide detailed data about the pharmacokinetics of SER at precise increments of time after observed administration of the drug, allowing for a more * 2008 Lippincott Williams & Wilkins Copyright @ 2008 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 651 Freeman et al Journal of Clinical Psychopharmacology Volume 28, Number 6, December 2008 comprehensive picture of the pharmacokinetics, with substantiated adherence to the protocol. Treatment guidelines for the acute and maintenance treatment of MDD during pregnancy and postpartum are urgently needed. Much of the focus to date has been on safety of in utero exposure to the baby, but data are also necessary to inform dosing of medication, efficacy of antidepressants, and monitoring guidelines. If patients are to be treated with antidepressant medication, it is prudent to use the lowest possible dose to minimize risks of exposure to the baby, but not to the extent of sacrificing optimal outcomes with regard to maternal depression treatment. Our results support that additional clinical monitoring is advisable for women treated with antidepressants during pregnancy, especially in the third trimester, as serum concentrations are likely to decrease somewhat for most women. Although many women may not experience clinically important pharmacokinetic changes in late pregnancy, the heterogeneity of such changes we observed suggests that individual women may indeed experience changes that necessitate careful monitoring of clinical condition and appropriate treatment modifications. At this time, there is a substantial need for evidencebased guidelines to inform the treatment of major depression in women during pregnancy and postpartum. Similar to the increased frequency of obstetric visits in late pregnancy based on medical need, women with MDD should have mood assessments with increased frequency as pregnancy progresses. In fact, it would be prudent and convenient to consider assessing depressive symptoms in coordination with prenatal care visits, which generally increase in frequency during late pregnancy, overlapping with the observed points with greatest likelihood of diminished antidepressant serum levels. We observed a substantial degree of heterogeneity in pharmacokinetic data between individuals. We suspect that genetically determined factors pertaining to drug metabolism were involved in the observed heterogeneity. Sertraline is extensively metabolized, and multiple CYP isozymes are involved in the metabolism of SER including the polymorphically distributed isozymes CYP2D6, CYP2C9, CYP2B6, CYP2C19, and CYP3A4.31–34 Calculating the contribution from specific isoforms onto the clearance of SER has proven a complicated task. Metabolism and clearance of SER are consistent with a high hepatic extraction. The initial pathway involves N-demethylation to the active metabolite, NOR. Norsertraline has a plasma elimination half-life of 62 to 104 hours. Both SER and NOR undergo oxidative deamination, followed by reduction, hydroxylation, and glucuronide conjugation. Genetic assessments may be important in future studies of pharmacokinetics in pregnant and postpartum women. Pregnancy is a condition characterized by high serum estrogen concentrations, which may affect the activity of various CYP isoforms potentially affecting clearance.35 Therefore, future studies might also explore the relationship of estrogen and SER levels during the third trimester and the mediating role of CYP2D6. The foremost limitation of this study is the small sample size. We initially intended to include 20 women, but enrolled 11. Six women completed at least 2 GCRC visits, allowing us 652 to collect serial blood samples under controlled conditions for 2 points of comparison during pregnancy. We found several factors contributed to difficult recruitment and retention. Over the course of the study, new information regarding potential risks of SSRIs was reported, and the US FDA (the sponsor of this study) issued warnings about the use of antidepressants during pregnancy, including a black-box warning. Subsequent to the labeling change, health care providers in our community were increasingly uncomfortable prescribing antidepressants for pregnant women. In addition, many of the women who participated in the study found the lengthy GCRC visits prohibitive to continuing participation, although we were able to reimburse participants for their time and additionally for child care if necessary. Also, our protocol prohibited concurrent medications with few exceptions. There were interested potential participants who could not enroll in the study because of concurrent psychotropic medication use or high-risk pregnancies. Other groups of investigators have experienced similar challenges as we did in recruitment and retention of pregnant and postpartum women. In recent treatment studies in pregnant and postpartum women with MDD, researchers in this area have found that enrollment and retention are challenging in this population.36,37 In a longitudinal study by Sit et al,16 single blood samples were obtained longitudinally during pregnancy and postpartum. In their study, of 11 subjects enrolled, the protocol required single blood draws at 7 points (20, 30, and 36 weeks during pregnancy, at delivery, and at 2, 4, 5, 6, and 12 weeks postpartum). None of the participants completed all of the sampling times, and 5 of 11 did not have the final 12-week blood draw data. The study by Sit et al16 represents the largest longitudinal study to date on this topic, and the authors found that most women using SSRIs in that study experienced decreased mean dose plasma concentrations in late pregnancy. Similar to our findings, this was not universally observed for all participants, and there may be individual differences in the impact of pregnancy on the pharmacokinetics of antidepressants. An important limitation in the interpretation of pharmacodynamic data was the heterogeneity of course of MDD. We did not require that participants meet the criteria for a current major depressive episode nor be in remission at the time of intake. Therefore, the course of the disorder between patients and correlated with pharmacokinetic data is difficult to compare across study visits. Future directions of study are required to advise dosing and monitoring of antidepressants during pregnancy and postpartum. Further study is required, and additional data are needed to include the role of genetics, implications of polypharmacy, and the clinical implications of pharmacokinetic changes associated with pregnancy. AUTHOR DISCLOSURE INFORMATION Marlene P. Freeman, MD: US FDA, research support (for investigator-initiated trials) from GlaxoSmithKline, Lilly, Forest; honoraria for CME development from Chatham Institute (grant from KV Pharmaceuticals). Karen Fried, BA, Marietta Anthony, PhD, Raymond L. Woosley, MD, PhD, report nothing to disclose. Melinda F. Davis, PhD: research support * 2008 Lippincott Williams & Wilkins Copyright @ 2008 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Journal of Clinical Psychopharmacology Volume 28, Number 6, December 2008 from National Science Foundation, WOMB Foundation (Watching Over Mothers and Babies), CDC, McKnight Associates, consulting firm subcontracting for CDC). Martha Fankhauser, MS Pharm: speakers’ bureau at Forest Pharmaceuticals Inc, AstraZeneca Pharmaceuticals LP. Francisco Moreno, MD: research funding, consulting, and speaking honoraria from Cyberonics Inc; speaker and consultant for Bristol-Myers Squibb and Otsuka Pharmaceuticals; consultant for Forest; contract (clinical trial) with Novartis; pending contracts for research with CORCEPT, Pfizer, and Sepracor. Paul E. Nolan Jr, PharmD: research support from Medical Carbon Research Institute, NovoNordisk, Medicure, Inc, Syncardia Systems, Inc, and ThromboVision, Inc; honoraria or travel support for consulting from Syncardia Systems, Inc, Abiomed, Inc, CV Therapeutics, and Abbott Laboratories. REFERENCES 1. Dietz PM, Williams SB, Callaghan WM, et al. Clinically identified maternal depression before, during, and after pregnancies ending in live births. Am J Psychiatry. 2007;164:1515–1520. 2. Gaynes BN, Gavin N, Meltzer-Brody S, et al. Perinatal depression: prevalence, screening accuracy, and screening outcomes. Evidence Report/ Technology Assessment No. 119. 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