For many women with bipolar disorder, lamotrigine (Lamictal) is an effective mood stabilizer. Given its favorable reproductive safety profile, lamotrigine (LTG) 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 same dose of medication that has kept them well prior to pregnancy. Reducing the dosage of medication may result in sub-therapeutic levels, which may in turn 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 during pregnancy.
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 32 (Pennell et al, 2004).
Should the Dose Be Adjusted During Pregnancy?
While our group does not typically increase the dose of lamotrigine during pregnancy in the absence of clinical changes. Some clinicians increase the dosage of lamotrigine during pregnancy to maintain pre-pregnancy blood levels in patients with bipolar disorder. For example, Clark and colleagues use an approach modeled after the management of seizure disorders and recommend adjusting lamotrigine dosing during pregnancy according to blood levels.
In alignment with the recommendations of lamotrigine dosing in women with epilepsy, Clark recommends that prior to pregnancy, a reference LTG plasma concentration should be obtained. During pregnancy, plasma concentrations of LTG should be measured every 4 weeks, and the dose should be increased by 20-25% if LTG levels fall below the pre-pregnancy level. After delivery, the plasma concentration of LTG should be measured within the first or second week, and the dose should be reduced by 20-25% and the procedure repeated until pre-pregnancy levels are re-established.
Lamotrigine serum levels return to pre-pregnancy 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.
In a response to this article, Sharma and colleagues questioned this approach, as there is no evidence to indicate that lower blood levels of lamotrigine are associated with increased risk for relapse. Sharma also noted that if symptoms were to 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. Higher lamotrigine doses used during pregnancy, especially if not clinically warranted, may also increase risk for neonatal toxicity.
Making Decisions in the Absence of Clear Guidelines
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 contrast to mood stabilizers like lithium, where there is a defined therapeutic range for blood levels, there is no such guideline for dosing lamotrigine.
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 if there is any change in symptoms; 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
References:
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.
Newport DJ, Stowe ZN, Viguera AC, Calamaras MR, Juric S, Knight B, Pennell PB, Baldessarini RJ. Lamotrigine in bipolar disorder: efficacy during pregnancy. Bipolar Disorders 2008;10:432-436.
Pennell PB, Newport DJ, Stowe ZN, Helmers SL, Monbomery JQ and Henry TR. The impact of pregnancy and childbirth on the metabolism of lamotrigine. Neurology 2004;62:292-295.
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.
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