To the Editor: Levetiracetam is a novel antiepileptic drug with antikindling properties but no known mechanism that directly affects inhibitory neurotransmitters or excitatory amino acids. Although a number of newer anticonvulsants have begun to receive attention for their possible antimanic and/or antidepressant efficacy, we know of no published reports regarding these potential properties of levetiracetam. We report a patient with acute mania that stabilized with open-label levetiracetam monotherapy, recurred after drug cessation, and restabilized after drug reintroduction.
Mr. A was a 42-year-old divorced white man with a 27-year history of nonrapid-cycling bipolar I disorder. He had no psychiatric comorbidities according to the Structured Clinical Interview for DSM-IV (1) a 2–3 month history of elevated mood, pressured speech, sleeplessness, and related symptoms, and subthreshold depression (a baseline score of 25 on the Young Mania Rating Scale  and a score of 16 on the 31-item Hamilton Depression Rating Scale). Mr. A had experienced his first manic episode at age 15 and his first depressive episode at age 35. He had four lifetime psychiatric hospitalizations and had attempted suicide at age 39. Previous episodes had been modestly responsive to adequate trials of lithium, divalproex, carbamazepine, conventional neuroleptics, selective serotonin reuptake inhibitors, and/or psychostimulants. A 6-week trial of 1000 mg/day of divalproex and 15 mg/day of olanzapine was discontinued because of sedation and nausea, after only partial improvement of his current mania.
Levetiracetam was prescribed to Mr. A at 500 mg/day and increased by 500 mg/day over 5 weeks to 2500 mg/day. His score on the Young Mania Rating Scale decreased to 6, his score on the Hamilton depression scale decreased to 5, and he experienced no side effects. A 50% reduction in score from baseline on the Young Mania Rating Scale was seen at week 3. Euthymia was sustained for 3 weeks, until Mr. A missed 6 days of drug therapy after he missed an appointment. He was seen subsequently with reemergent mania, a score of 22 on the Young Mania Rating Scale, and a score of 22 on the Hamilton depression scale. His mania again was ameliorated after he started taking levetiracetam, 2500 mg/day. There were no further recurrences of mania by the 6-week follow-up.
Although the patient’s drug discontinuation was unplanned, the swift resolution of reemergent mania after abrupt cessation was striking. The high degree of tolerability and favorable side effect profile of levetiracetam suggests it may be useful, in light of the high rates of noncompliance with many existing pharmacotherapies for bipolar disorder. Current neuropsychopharmacologic theories emphasize the importance of the upregulation of γ-aminobutyric acid (GABA) and the lowering of excitatory amino acids to explain the occurrence of mood stabilization with anticonvulsants. Newer anticonvulsants often become regarded as good candidates for mood stabilizers on the basis of these mechanisms. However, negative studies of the use of gabapentin (3) and tiagabine (4) to treat mania call into question such generalizations and suggest that additional mechanisms may be involved. The unique neuropharmacology of levetiracetam, combined with the present observations, warrant controlled studies to investigate further its possible thymoleptic properties. Pending further reports, these findings regarding one patient must be interpreted with caution.