REVIEW OF: Zarezadeh F et al, Int Clin Psychopharmacol 2022;37(2):46–53

STUDY TYPE: Randomized double-blind placebo-controlled trial

Among the anticonvulsants, a few have passed in mania (carbamazepine, valproate), others have failed (lamotrigine, gabapentin, topiramate), and others remain untested. Levetiracetam (Keppra) is one of those unknowns. It failed in a controlled trial of bipolar depression, and the current study is the first controlled trial to test it in mania.

The investigators randomized 40 outpatients (mean age 40 years) with active mania to receive either levetiracetam plus quetiapine or placebo plus quetiapine. The patients had become noncompliant with their maintenance therapy one to two weeks before the trial began, but they were not specifically treatment resistant. They scored at least 20 (mean of 37) on the 60-point Young Mania Rating Scale (YMRS) and had an average of three to four past manic episodes. Those with a history of rapid cycling or with active suicidal planning or substance use disorders were excluded.

The two medications were started simultaneously as 1) levetiracetam 20 mg/kg/day for four weeks then 50 mg/kg/day for the final two weeks; and 2) quetiapine 100 mg/day for two weeks then 300 mg/day for the final four weeks (below quetiapine’s typical range of 400–800 mg for mania). The primary outcome was the change in YMRS scores over the six-week trial. Secondary measures assessed tolerability along with a specific rating scale for suicidality.

The results were inconclusive. At the six-week mark, which was the primary outcome measure, the percent reduction in YMRS scores was just on the fence of statistical significance (50.37% for levetiracetam vs 40.33% for placebo; p=0.059). Close, but no cigar. Levetiracetam did separate from placebo at the four-week mark as well as on secondary outcomes of response rate (>50% reduction on YMRS; 52.6% vs 19.0%; p=0.046) and time x treatment interaction (p=0.04).

Although the study detected no problems with tolerability or suicidality on the drug, levetiracetam does carry a warning about adverse psychiatric effects, including aggression, depression, psychosis, and even mania. Severe dermatologic reactions are also possible, but the most common side effects are fatigue, headache, and dizziness. Levetiracetam is a low-cost generic with a favorable cognitive profile and low rates of weight gain.

CARLAT TAKE

With benefits that are statistically suspect and psychiatric risks that give us pause, we’re not yet ready to endorse levetiracetam augmentation in mania.