Rationale and Design for an Investigation to Optimize Selective Serotonin Reuptake Inhibitor Treatment for Pregnant Women with Depression MJ Avram 1 , CS Stika 2 , LJ Rasmussen-Torvik 3 , JD Ciolino 3 , E Pinheiro 4 , AL George Jr 5 and KL Wisner 4 The physiological changes of pregnancy can affect the pharmacokinetics of a drug, thereby affecting its dose requirements. Because pharmacokinetic (PK) studies in pregnant women have rarely been conducted, evidence-based dosing adjustments are sel- dom available. In particular, despite the fact that the use of antide- pressants has become increasingly common, pregnancy-associated PK changes of the selective serotonin reuptake inhibitors (SSRIs) are largely unknown. THE LAST TRUE THERAPEUTIC ORPHAN The pregnant woman has been called “the last true therapeutic orphan.” 1 Indeed, pregnant women (and women of child-bearing potential) have historically been excluded from clinical trials because of the well-intentioned attempt to protect the vulnerable fetus. 2 Unfortunately, an unintended consequence has been an informa- tion gap that makes prescribing drugs for pregnant women with pre- existing illnesses or new-onset disorders difficult and potentially dangerous for both the mother and the fetus. 1,2 In the absence of knowledge regarding changes in the pharmacokinetics of a drug pro- duced by the physiological changes of pregnancy, healthcare profes- sionals often prescribe a standard adult dose for pregnant women. The resulting plasma drug concentrations may be subtherapeutic if its elimination clearance is increased in pregnancy or supratherapeu- tic if the elimination clearance is decreased. Subtherapeutic concen- trations at steady-state may not only result in the return of the mother’s symptoms, which could pose a risk to the fetus, but also add the risk of fetal drug exposure without the benefit of maternal therapeutic efficacy. Supratherapeutic drug concentrations confer no additional therapeutic benefit to the mother and may cause adverse drug reactions in the mother and be toxic to the fetus. PHYSIOLOGICAL CHANGES IN PREGNANCY A number of physiological changes occur during pregnancy that affect the pharmacokinetics of drugs. Total body weight increases, due to a substantial (6 to 8 L) increase in the volume of water found within the intravascular and the extravascular fluid spaces, which leads to a significant increase in the volume of distribution of hydrophilic drugs, and an increase in body fat, which increases the volume of distribution of lipophilic drugs. 1,2 These increases in volume of distribution are likely to decrease peak concentra- tions and increase the elimination half-life of drugs. Cardiac out- put increases by 50% early in pregnancy and the resulting changes in regional blood flow can affect both the distribution and elimination of drugs. 1 Among the most important of these effects is the 50% to 80% increase in effective renal plasma flow that increases glomerular filtration rate and the clearance of drugs eliminated by the kidneys. 2 Another potentially important conse- quence of the increased cardiac output is the increase in hepatic blood flow, which affects the clearance of drugs with high hepatic extraction ratios. 1 But of all of the physiological changes that affect the pharmacokinetics of drugs, perhaps the most important of these during pregnancy is the change in drug metabolizing enzymes. Pregnancy affects the enzymes responsible for drug metabolism in different ways. 3 Activation of the pregnane X receptor (PXR) by elevated progesterone concentrations has been proposed as the mechanism for the observed increase in CYP3A4, CYP2C9, and CYP2A6 activity. The activity of CYP2D6 is also increased, but the mechanism has not been fully elucidated. The increase in uri- dine 5 0 -diphosphate glucuronosyltransferase 1A1 (UGT1A1) activity appears to be triggered by increased progesterone; whereas the increase in UGT1A4 activity is tied to elevated estra- diol concentrations. Estrogen may also be responsible for the 1 Northwestern University Feinberg School of Medicine, Department of Anesthesiology, Chicago, Illinois, USA; 2 Northwestern University Feinberg School of Medicine, Department of Obstetrics and Gynecology, Chicago, Illinois, USA; 3 Northwestern University Feinberg School of Medicine, Department of Preventive Medicine, Chicago, Illinois, USA; 4 Northwestern University Feinberg School of Medicine, Department of Psychiatry and Behavioral Sciences, Chicago, Illinois, USA; 5 Northwestern University Feinberg School of Medicine, Department of Pharmacology, Chicago, Illinois, USA. Correspondence: KL Wisner (katherine. wisner@northwestern.edu) Received 12 January 2016; accepted 27 March 2016; advance online publication 2 April 2016. doi:10.1002/cpt.375 CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 100 NUMBER 1 | JULY 2016 31 DEVELOPMENT