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

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.

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).

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).

This was a small open-label pilot study with use of varied concomitant pharmacotherapies and no placebo comparator.

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.