Pancytopenia and Valproic Acid: A Dose‐related Association

To the Editor: The first report of the therapeutic effects of valproic acid in bipolar disorder appeared in France in 1966.1 Several studies have provided convincing evidence of its efficacy in acute mania and possibly maintenance therapy in bipolar disorder.2,3 Valproic acid is generally well tolerated, with an acceptably low incidence of adverse effects and a favorable side effect profile compared with other antiepileptic, lithium, and antipsychotic agents.4,5 However, in addition to its relatively benign side effects, valproic acid has been associated with severe and potentially fatal adverse effects. Common dose-related side effects include; anorexia, nausea, dyspepsia, indigestion, vomiting, diarrhea, benign hepatic transaminase elevations, tremor, and sedation.6 Potentially fatal reactions include blood dyscrasias and pancreatitis. We report a case of subclinical valproic acid dose-related pancytopenia in an adult. Mr. K is a 65-year-old man with a 44-year history of DSM IV bipolar mood disorder. His illness was noted when he was 21, and he has since been hospitalized several times. He continued to function relatively well between episodes without any significant interepisode residual symptoms until 1992 when lithium was withdrawn because of renal complications, and carbamazepine treatment was unsuccessful because of poor tolerance. His bipolar mood disorder course worsened after 1992, with several mixed episodes and interepisode residual hypomania. He was treated with moclobemide and clonazepam until August 1997, at which time he was prescribed valproic acid by one of the authors. There was no history of medical problems or other treatments that may have increased the risk of hematological complications. Low-dose enalapril was administered for hypertension. Mr. K responded well to valproic acid 750 mg/day for 10 weeks, followed by a dosage increase to 1000 mg/day with serum levels between 319 and 496 μmol/L. Moclobemide and clonazepam were withdrawn gradually over 8 weeks. Pre-valproic acid hematological indices were WBC 6.8, RBC 4.52, and PLT 160. After 10 weeks of treatment with valproic acid, at 750 mg/day, the patient's laboratory indices were WBC 4.7, RBC 4.21, and PLT 137. These same indices after 14 weeks of valproic acid, 4 weeks at 1000 mg/day, were WBC 3.5, RBC 4.18, and PLT 132. The laboratory indices continued to fluctuate with a downward trend. The lowest indices before valproic acid discontinuation were WBC 3.2, RBC 3.83, and PLT 106. In an otherwise unremarkable review of symptoms and adverse effects during this period, the patient experienced new onset flu-like symptoms, headaches, and weakness. He agreed to a gradual discontinuation of the valproic acid and substitution with lamotrigine. Hematological indices normalized within 4 weeks of valproic acid discontinuation; his flu-like symptoms, headache, and weakness also resolved. Our patient seemed to demonstrate a dose-dependent, mild, and reversible suppression of all three blood cell lines. Hematological abnormalities have been reported with long-term use of valproic acid. Thrombocytopenia and macrocytosis are the most common findings.7 Most studies have been conducted on children and adolescents.8 Severe blood dyscrasias, though uncommon, have been reported in psychiatric patients given carbamazepine and valproic acid.9 Medication-induced blood dyscrasia, pluripotential stem cells suppression related to pancytopenia, and an immunological response evoked by valproic acid have all been proposed as hematologic abnormality mechanisms.10,11 Circulating antibodies of immunoglobulin M type (IgM) have also been suggested as a possible etiology.12 In one case report, bone marrow examination in a patient with valproic acid-induced pancytopenia revealed hypocellularity with some dyserythropoietic features.10 In one case report, a direct Coombs test, initially positive, became negative after the discontinuation of valproic acid. These findings suggest drug-induced bone-marrow toxicity.13 We did not conduct biopsy evaluation of our patient's bone marrow. Robinson et al. have proposed that age, illness, and medications may create a synergistic vulnerability to hemopoietic disorders.14 Duration of exposure and dose of valproic acid may also be significant risk factors in the development of valproic acid-induced pancytopenia. Our case was identified only from routine monitoring of blood cells. Tohen et al. have suggested that routine blood monitoring of valproic acid may not be cost-effective considering the low rate of adverse hematological effects.9 Following this recommendation, our patient could have progressed to anemia, coagulation abnormalities, and/or infection before this toxicity was detected. This case illustrates that without routine blood monitoring, it is essential for physicians to clinically monitor for and inform patients about the signs and symptoms of reduced blood cell counts. We think there is a need for the development of an efficient and effective strategy to identify hematologically compromised patients receiving valproic acid.