A preliminary open trial of nefazodone added to mood stabilizers for bipolar depression.

BACKGROUND: Little information exists on the use of nefazodone to treat bipolar depression. We hypothesized that nefazodone added to a standard mood stabilizer would show significant antidepressant efficacy with minimal agitation or induction of mania, by virtue of its selective 5-HT(2A) blockade. METHODS: Thirteen DSM-IV pure depressed-phase nonpsychotic bipolar outpatients received an open-label 8-week pilot trial of flexibly dosed nefazodone (mean±SD peak dose=462.5±164.0mg/day) with a concurrent mood stabilizer or atypical antipsychotic. Primary outcomes included the Hamilton Rating Scale for Depression (HAM-D) and Clinical Global Impressions Severity Scale (CGI-S). RESULTS: All subjects completed at least 4 weeks of treatment, while 9 (69%) completed the 8-week protocol. Based on last observation point, 8 (62%) had at least a 50% reduction from baseline HAM-D scores. Significant improvement from baseline was observed in both HAM-D (z=2.05, p=.04) and CGI severity ratings (z=2.21, p=.03). Induction of mania occurred in 1 subject (7%). No subjects manifested clinical signs of hepatic failure, and none prematurely terminated the study due to other adverse events (most common side effects included fatigue, insomnia, nausea, or headache). LIMITATIONS: This was a small open-label pilot study with use of varied concomitant pharmacotherapies and no placebo comparator. CONCLUSIONS: While nefazodone is seldom used in clinical practice due to concerns about rare but severe hepatotoxicity, it may represent a model for postsynaptic 5HT(2A) antagonism that mechanistically could help to inform the development of future treatments for bipolar depression.