Lamotrigine-Induced Neutropenia in a Woman With Schizoaffective Disorder

Sir: Lamotrigine is a drug of the phenyltriazine class with inhibitory effects on voltage-sensitive sodium channels along with modulating effects on calcium and potassium channels. Lamotrigine is also a weak dihydrofolate reductase inhibitor. The drug is currently approved by the U.S. Food and Drug Administration for maintenance treatment in bipolar type I disorder. There have been reports of hematologic adverse effects with lamotrigine therapy.^1–8 We report a case of a 50-year-old woman with schizoaffective disorder who presented with neutropenia while on lamotrigine therapy.

Case report

Ms. A, a 50-year-old African American woman with DSM-IV schizoaffective disorder, presented in 2003 with mood swings, alopecia, and weight gain during treatment with 1000 mg/day of sodium valproate therapy. After a discussion of available choices, a decision to cross-taper and switch her to lamotrigine was made. Lamotrigine was initiated at 12.5 mg once daily for 2 weeks and was increased to 25 mg once daily for 2 weeks and then increased by 50 mg every 2 weeks until she was receiving lamotrigine 150 mg twice daily. Sodium valproate was tapered over a week. The patient tolerated the switch well and reported a significant improvement in mood symptoms. Her white blood cell (WBC) count and absolute neutrophil count (ANC) prior to lamotrigine therapy were 4.9 × 10⁹/L (reference range, 4–11 × 10⁹/L) and 2.8 × 10⁹/L (reference range, 1.7–7 × 10⁹/L), respectively.

However, 2 months later, a routine complete blood cell (CBC) count revealed a WBC count of 3.8 × 10⁹/L and an ANC count of 2.2 × 10⁹/L. Ms. A did not demonstrate any clinical signs or symptoms of leukopenia, and the rest of her laboratory results were unremarkable. Medical illnesses and medications associated with leukopenia were ruled out. On the basis of her robust therapeutic response to lamotrigine and the lack of clinical signs and symptoms of neutropenia, a decision to continue lamotrigine therapy was made. Regular CBC counts were obtained to monitor the leukopenia.

Approximately 4 months later, based on declining blood counts, a decision to decrease lamotrigine by 50 mg/day was made. Following the dose reduction, her counts briefly went back to baseline level; however, they soon resumed a downward trend. Finally, a decision to discontinue lamotrigine was made after Ms. A had been on treatment with the drug for approximately 10 months. Her WBC count and ANC at drug discontinuation were 2.8 × 10⁹/L and 1.5 × 10⁹/L, respectively. Subsequent WBC count and ANC readings returned to baseline level in a few weeks without any recurrence of neutropenia.

Approximately a year and half later, Ms. A moved to another state, where a retrial of lamotrigine 100 mg once daily was attempted. At that time, her leukocyte and neutrophil counts decreased from 3.5 × 10⁹/L and 1.9 × 10⁹/L before therapy to 2.6 × 10⁹/L before therapy to 1.5 × 10⁹/L after 2 months of lamotrigine therapy. Again, after drug discontinuation, her counts returned to baseline over a period of approximately 6 weeks. Her counts have been stable since then. While the patient was receiving lamotrigine, hematologic adverse effects from concomitant medications or medical conditions were ruled out. The platelet counts and red blood cell counts remained within normal limits throughout this period.

Published reports of lamotrigine-induced neutropenia^1–4 and agranulocytosis^5–8 have demonstrated normalization of blood counts with drug discontinuation alone. In our case, there was a definite association between lamotrigine therapy and neutropenia. The brief normalization of blood counts following dose reduction of lamotrigine and the on-off-on trial further support the cause-and-effect relationship. Other risk factors for lamotrigine-induced hematologic adverse effects such as concomitant anticonvulsants or exceeding the recommended starting dose or titration were absent in our case. Although our patient was African American, benign ethnic neutropenia was an unlikely cause of the observed effect as the variations in counts were observed with drug rechallenge and discontinuation.

Although the mechanism of action of lamotrigine-induced hematologic abnormalities is unknown, a combination of immunoallergic, direct medullary toxicity, and granulopoiesis-inhibiting effects has been suggested.¹ There are also reports on lamotrigine-associated macrocytic anemia,⁹ leukopenia,^10–12 and thrombocytopenia,¹² which suggest a common possible mechanism involving enzymatic inhibition of dihydrofolate reductase by lamotrigine. It is plausible that one or more of the above pathophysiologic mechanisms were involved in our patient. With the normalization of blood counts with discontinuation alone, we did not attempt a bone marrow aspiration.

Our case demonstrates a combination of unique features: a dose-dependent variation in WBC count and ANC, gradual development of neutropenia, as well as the outcome of a rechallenge. To our knowledge, these features have not been reported in the same patient. In any event, our case report provides more evidence to corroborate this rare but dangerous side effect and emphasizes the need for frequent monitoring of blood counts during lamotrigine therapy.