For many women with bipolar disorder, lamotrigine (Lamictal) is an effective mood stabilizer. Given its favorable reproductive safety profile, lamotrigine is a reasonable option for women who require treatment with a mood stabilizer during pregnancy.
When advising women regarding the use of medications during pregnancy, we typically recommend that women remain on the dose of medication that has kept them well prior to pregnancy. Reducing the dosage of medication may result in sub-therapeutic levels, which may increase the risk of relapse during pregnancy despite maintenance of the medication.
Maintenance of adequate dosage during pregnancy is especially important; there are data to indicate that levels of many medications may decrease during pregnancy due to changes in fluid volume and increases in hepatic metabolism. Lamotrigine levels can decline significantly during pregnancy. Estrogen increases the clearance of lamotrigine by inducing the liver enzymes involved in its metabolism. Thus, more rapid metabolism can result in lower, and possibly sub-therapeutic, levels of lamotrigine.
As estrogen levels gradually rise over the course of pregnancy, lamotrigine levels may drop by as much as 50%. As there is substantial variability in lamotrigine clearance between individuals, some women may experience a large drop in lamotrigine blood levels during pregnancy while others may experience a more modest decline. In the setting of falling levels, some women may experience clinical destabilization.
A recent study indicates that increases in lamotrigine clearance can begin as early as 5 weeks gestational age, often before women are aware that they are pregnant, and clearance continues to increase through gestational week 13.
Recommendations for Dose Adjustment
Most of our data on this topic comes from women taking lamotrigine for the management of seizure disorders during pregnancy. A recent article proposed the following guidelines for adjusting lamotrigine (LTG) dose during pregnancy and the postpartum period.
- Prior to pregnancy, obtain a reference LTG plasma concentration (RC).
- After conception, plasma concentrations of LTG should be measured every 4 weeks.
- If the LTG plasma concentration falls below the RC, the dose of LTG should be increased by 20-25%.
- After delivery, the plasma concentration of LTG should be measured within the first or second week.
- If the LTG plasma concentration is higher than the RC, the LTG dose should be reduced by 20-25% and the procedure repeated until RC is re-established.
While there is no reason to believe that women with bipolar disorder metabolize lamotrigine differently than women with epilepsy, many psychiatrists do not routinely adjust lamotrigine doses during pregnancy. Because there is no established therapeutic blood level for lamotrigine, information gleaned by blood level monitoring may be difficult to interpret.
For women taking lamotrigine prior to pregnancy, a pre-pregnancy blood level of lamotrigine may be established as a baseline and subsequently used as a guideline for dosing during pregnancy. However, careful monitoring of clinical symptoms may be equally as effective in managing dose adjustments as measuring blood levels during pregnancy and the postpartum period.
Lamotrigine serum levels return to prepregnancy values within 3 to 4 weeks after delivery. If the dose of lamotrigine was increased substantially during pregnancy, the patient should be monitored for any signs of toxicity (e.g. nausea, dizziness, vision changes, altered mental status) during the first few weeks after delivery, and the dose should gradually be decreased to pre-pregnancy levels.
Lingering Controversies
Where our group typically does not increase the dose of lamotrigine prophylactically in women with bipolar disorder, Clark and colleagues use an approach modelled after the management of seizure disorders and recommend adjusting lamotrigine dosing during pregnancy according to blood levels. However, in a response to this article, Sharma and colleagues questioned this approach, as there was no evidence in this small case series to indicate that lower blood levels of lamotrigine were associated with relapse. They also noted that if recurrent symptoms do emerge during pregnancy, other medications, such as the atypical antipsychotics, may prove to be more effective than lamotrigine for managing sleep disruption, hypomania or mania and may also act more quickly.
In patients with seizure disorders, blood levels of lamotrigine in a given individual are strongly correlated with seizure control. However, in patients with bipolar disorder, there is more likely a broader range of therapeutic blood levels for lamotrigine. Thus, women may be able to tolerate fluctuations in LTG levels during pregnancy without significant risk for relapse. In patients who present prior to pregnancy, it may be helpful to measure a baseline serum LTG level to guide dosing decisions later on during pregnancy; however, we do not have clear evidence at this point to indicate that tight control of lamotrigine levels during pregnancy is required or if this approach decreases the risk of relapse. Following the patient’s symptoms closely and making medication adjustments as needed allows us to use lower doses of medication; however, in patients who are very sensitive to changes in LTG dosage, closer monitoring of LTG blood levels may be preferable.
Ruta Nonacs, MD PhD
Clark CT, Klein AM, Perel JM, Helsel J, Wisner KL. Lamotrigine dosing for pregnant patients with bipolar disorder. Am J Psychiatry. 2013 Nov 1;170(11):1240-7.
Fotopoulou C, Kretz R, Bauer S, Schefold JC, Schmitz B, Dudenhausen JW, Henrich W. Prospectively assessed changes in lamotrigine-concentration in women with epilepsy during pregnancy, lactation and the neonatal period. Epilepsy Res. 2009 Jul;85(1):60-4.
Karanam A, Pennell PB, French JA, Harden CL, Allien S, Lau C, Barnard S, Callisto SP, Birnbaum AK. Lamotrigine clearance increases by 5 weeks gestational age: Relationship to estradiol concentrations and gestational age. Ann Neurol. 2018 Oct;84(4):556-563.
Sabers A. Algorithm for lamotrigine dose adjustment before, during, and after pregnancy. Acta Neurol Scand. 2012 Jul;126(1):e1-4.
Sharma V, Sommerdyk C. Management issues during pregnancy in women with bipolar disorder. Am J Psychiatry. 2014 Mar;171(3):370-1.