Pharmacotherapy for Mood Disorders in Pregnancy

Abstract

Objective Pharmacotherapy for mood disorders during pregnancy is often complicated by pregnancy-related pharmacokinetic changes and the need for dose adjustments. The objectives of this review are to summarize the evidence for change in perinatal pharmacokinetics of commonly used pharmacotherapies for mood disorders, discuss the implications for clinical and therapeutic drug monitoring (TDM), and make clinical recommendations. Methods The English-language literature indexed on MEDLINE/PubMed was searched for original observational studies (controlled and uncontrolled, prospective and retrospective), case reports, and case series that evaluated or described pharmacokinetic changes or TDM during pregnancy or the postpartum period. Results Pregnancy-associated changes in absorption, distribution, metabolism, and elimination may result in lowered psychotropic drug levels and possible treatment effects, particularly in late pregnancy. Mechanisms include changes in both phase 1 hepatic cytochrome P450 and phase 2 uridine diphosphate glucuronosyltransferase enzyme activities, changes in hepatic and renal blood flow, and glomerular filtration rate. Therapeutic drug monitoring, in combination with clinical monitoring, is indicated for tricyclic antidepressants and mood stabilizers during the perinatal period. Conclusions Substantial pharmacokinetic changes can occur during pregnancy in a number of commonly used antidepressants and mood stabilizers. Dose increases may be indicated for antidepressants including citalopram, clomipramine, imipramine, fluoxetine, fluvoxamine, nortriptyline, paroxetine, and sertraline, especially late in pregnancy. Antenatal dose increases may also be needed for lithium, lamotrigine, and valproic acid because of perinatal changes in metabolism. Close clinical monitoring of perinatal mood disorders and TDM of tricyclic antidepressants and mood stabilizers are recommended.

Effect of Cytochrome P450 (CYP) 2D6 Genetic Polymorphism on the Inhibitory Action of Antidepressants on CYP2D6-Mediated Dopamine Formation from p-Tyramine

“…In addition, we previously reported that psychotropic drugs, such as imipramine, desipramine, and fluoxetine, inhibited 21-hydroxylation of progesterone and allopregnanolone (a neuroactive steroid) mediated by CYP2D6 and CYP2D4 (39). In the present study, we found that imipramine and desipramine, which are tricyclic antidepressants (22)(23)(24), competitively or noncompetitively inhibited dopamine formation from p-tyramine. However, the Ki values for CYP2D6.10 were higher than those for CYP2D6.1 (Fig.…”

“…These agents are metabolized to inactive 2-hydroxy compounds by CYP2D6 (24). To overcome the toxicity of older generation antidepressants, fluvoxamine, one of selective serotonin reuptake inhibitors (SSRIs), is widely used in the treatment of depression (22,23,25,26). Fluvoxamine is a weak inhibitor of CYP2D6, a moderate inhibitor of CYP2C19 and CYP3A4, and a potent inhibitor of CYP1A2; however, it is metabolized predominantly by CYP2D6 (27,28).…”

“…Imipramine and desipramine (a pharmacologically active N-demethylated metabolite biotransformed from imipramine by CYP1A2, CYP2C19, and CYP3A4) are older generation tricyclic antidepressants (22)(23)(24). These agents are metabolized to inactive 2-hydroxy compounds by CYP2D6 (24).…”

Pregnancy-Associated Changes in Pharmacokinetics: A Systematic Review

“…For some drug classes, a large number of PK clinical trials during pregnancy are available in the literature [29–34]. A recent review noted that, since 2008, about a third of these trials investigated drugs used in the treatment of acute labor and delivery issues, another third investigated drugs used in infectious disease treatment during pregnancy, and the remaining third investigated drugs used for various antepartum indications [35].…”

Maternal Pharmacokinetics and Fetal Disposition of (±)-Citalopram during Mouse Pregnancy

“…In the clinical setting, similar decreases in maternal plasma concentrations of CIT or other SSRIs have been suggested to cause reduced therapeutic efficacy of these drugs during pregnancy. 29−34,47 …”