We have an abundance of articles which address the impact of psychotropic medications on pregnancy.  Much less research, however, has focused on how pregnancy may affect how these medications work.  Physiologic changes take place during pregnancy which may affect the absorption, distribution, metabolism, and elimination of medications.  These pharmacokinetic changes may result in lower psychotropic drug levels and, in some cases, loss of clinical effectiveness.   A recent review summarizes how pregnancy affects the pharmacokinetics of psychotropic medications and provides guidelines for therapeutic drug monitoring.

This is a very thorough and clinically relevant article and definitely worth tracking down. In summary, drug levels may be affected by the following changes that take place during pregnancy:

Drug absorption is affected by slower gastric emptying and slower bowel and colonic transit time.

The increased plasma volume, change in protein binding, and lower ratio of lean muscle to adipose tissue during pregnancy may result in a greater volume of drug distribution for lipophilic drugs.

Hepatic metabolism of psychotropic medications is also altered due to pregnancy-associated changes in the activity of various metabolic enzymes.  Sex steroid levels increase during pregnancy and increase the activity of enzymes in the cytochrome P450 (CYP) family and Phase 2 metabolic enzymes such as uridine diphosphate glucuronosyltransferase (UGT).  This induction of activity may result in clinically significant reductions in active drug levels.

Increased renal blood flow and the associated increase in glomerular filtration rate (GFR) may increase drug elimination of certain medications during pregnancy.

There is evidence to indicate that the pharmacokinetics of the following medications may be affected during pregnancy:

Antidepressants:  SSRIs, SNRIS, Tricyclic Antidepressants (TCAs)

  • Metabolism mostly by the hepatic CYP enzymes
  • Antidepressant levels may fall, especially in late pregnancy (after 20 weeks)
  • No data on the pharmacokinetics of bupropion during pregnancy
  • Relapse of symptoms may necessitate increase in antidepressant dose
  • Therapeutic drug monitoring  of blood levels may be helpful for the TCAs
  • Blood levels typically do not correlate with clinical effectiveness of the non-TCA antidepressants, but it may be helpful to obtain a drug level prior to pregnancy as a guideline for adjusting dosage during pregnancy

Lithium

  • Increased glomerular filtration and increased fluid volume may reduce lithium levels during pregnancy.
  • At delivery, vascular volume rapidly decreases, and lithium clearance precipitously decreases to pre-pregnancy levels.
  • Blood levels may be used to adjust dosage with target range of 0.6 to 1.0 mEq/L, using the lowest possible effective dosage.

Lamotrigine (LTG)

  • Increased sex steroid levels increase phase 2 glucoronidation, which leads to increased LTG clearance.
  • LTG levels may decrease by 50% during pregnancy.
  • Within days of delivery, LTG elimination rate drops rapidly and plasma concentrations increase dramatically.
  • LTG levels may not correlate with clinical effectiveness, but it may be helpful to obtain a drug level prior to pregnancy as a guideline for adjusting dosage during pregnancy.

Carbamazepine (CBZ)

  • Total plasma concentrations of CBZ may be misleading; studies suggest that although the total concentration of CBZ decreases significantly in pregnancy, free-CBZ levels may not change when compared with baseline
  • Both free and plasma concentrations should be monitored.
  • The lowest effective dose should be used in pregnancy.
  • After delivery, the dose should be tapered rapidly to avoid toxicity and maintain pre-pregnancy CBZ levels.

Valproic Acid (VPA)

  • The plasma concentration of VPA decreases by as much as 50% during pregnancy; however, no significant changes have been found in unbound concentrations.
  • Free and plasma levels should be checked at least monthly to maintain preconception levels.
  • The lowest effective dosage of VPA, preferably less than 1000 mg/d, should be used in pregnancy, to reduce the risk of congenital malformation.

Ruta Nonacs, MD PhD

 

Deligiannidis KM, Byatt N, Freeman MP.  Pharmacotherapy for mood disorders in pregnancy: a review of pharmacokinetic changes and clinical recommendations for therapeutic drug monitoring.  J Clin Psychopharmacol. 2014 Apr;34(2): 244-55.