Research Article: Maximum Recommended Dosage of Lithium for Pregnant Women Based on a PBPK Model for Lithium Absorption

Date Published: May 30, 2012

Publisher: Hindawi Publishing Corporation

Author(s): Scott Horton, Amalie Tuerk, Daniel Cook, Jiadi Cook, Prasad Dhurjati.


Treatment of bipolar disorder with lithium therapy during pregnancy is a medical challenge. Bipolar disorder is more prevalent in women and its onset is often concurrent with peak reproductive age. Treatment typically involves administration of the element lithium, which has been classified as a class D drug (legal to use during pregnancy, but may cause birth defects) and is one of only thirty known teratogenic drugs. There is no clear recommendation in the literature on the maximum acceptable dosage regimen for pregnant, bipolar women. We recommend a maximum dosage regimen based on a physiologically based pharmacokinetic (PBPK) model. The model simulates the concentration of lithium in the organs and tissues of a pregnant woman and her fetus. First, we modeled time-dependent lithium concentration profiles resulting from lithium therapy known to have caused birth defects. Next, we identified maximum and average fetal lithium concentrations during treatment. Then, we developed a lithium therapy regimen to maximize the concentration of lithium in the mother’s brain, while maintaining the fetal concentration low enough to reduce the risk of birth defects. This maximum dosage regimen suggested by the model was 400 mg lithium three times per day.

Partial Text

Bipolar disorder, which affects approximately 1% of the population (mostly women), is a type of mood disorder which has periods of manic behavior and periods of depressive behavior. An overly joyful or overexcited state characterizes manic behavior; extremely sad and hopeless states characterize depressive behavior [1]. A standard treatment for bipolar disorder involves treatment with the element lithium, which was the first mood-stabilizing medication approved for treatment of “mania,” which later came to be known as bipolar disorder, in 1970 [2]. The brand names of bipolar lithium treatment drugs are Eskalith and Lithobid, which deliver lithium as lithium carbonate (Li2CO3). The typical size of a dose of lithium drug ranges from 900 to 1800 mg Li2CO3/day (if administered in 2 divided doses a day) and 900 to 2400 mg Li2CO3/day (if administered in 3-4 divided doses a day) [3]. Although the mechanism by which lithium mitigates the symptoms of bipolar disorder is not completely understood, lithium is thought to affect sodium transfer in the brain [4]. High doses can cause lithium poisoning and side effects such as the inability to control movement, blackouts, seizures, hallucinations, severe headaches, and acute renal failure [3, 5].

All simulations were performed using the MATLAB software suite. In the medical literature, bodily lithium concentrations are reported in milliequivalents lithium/mL tissue volume (mEq/mL); the unit mEq is equivalent to a millimol. In this paper, we utilize the units mEq to report bodily concentrations to be consistent with the medical literature. Dosages of lithium drugs are reported in milligram of the total drug, which is lithium carbonate (Li2CO3) for the brand name drugs Eskolith and Lithobid. Therefore, for example, a 300 mg tablet contains 8 mEq lithium.

This model has taken the first steps toward predicting the maximum acceptable lithium dosage regimen for pregnant bipolar women. Based on our simulation results and on clinical patient compliance, we recommend a maximum dosage regimen of three doses of 400 mg lithium evenly spaced over a 24-hour period. It is important to note that the maximum dosages recommended from the model are not necessarily nonpathological. These recommended dose regimens simply lower the average and peak values below concentrations known to be pathological. It is still important to take the lowest effective dosage of lithium to minimize the risk of birth defects. Hopefully, this paper has shed some light on what the maximum doses in a dosage regimen should look like to lower the risk of birth defects. Future research to improve the model could include determination of the fetal tissue to plasma lithium equilibrium ratio and collecting data on “safe” dosages of lithium that do not cause birth defects.