The efficacy of adjunctive N-acetylcysteine in acute bipolar depression: A randomized placebo-controlled study

•The study did not show a statistically significant difference based on the Montgomery-Asberg Depression Rating Scale (MADRS) score after 20 weeks of adjunctive N-acetylcysteine (NAC) treatment compared to placebo.•The MADRS score was reduced statistically significantly from baseline to week 20 in both study groups, and further reduced in the NAC study group at week 24.•The mania score increased in the NAC treated group as compared to the placebo group. To investigate the efficacy of adjunctive N-acetylcysteine (NAC) for the treatment of acute bipolar depression. A randomized, double-blind, multicentre, placebo-controlled trial including adult subjects diagnosed with bipolar disorder, currently experiencing a depressive episode. Participants were treated with 3 g/day NAC or placebo as an adjunctive to standard treatment for 20 weeks, followed by a 4-week washout where the blinding was maintained. The primary outcome was the mean change in the Montgomery Asberg Depression Rating Scale (MADRS) score over the 20-week treatment phase. Linear Mixed Effects Repeated Measures (LMERM) was used for analysing the primary outcome. A total of 80 subjects were included. The mean MADRS score at baseline was 30.1 and 28.8 in participants randomized to NAC and placebo, respectively. Regarding the primary outcome measure, the between-group difference (NAC vs. placebo) was 0.5, which was statistically non-significant (95% CI: -7.0-5.9;p = 0.88). All findings regarding secondary outcomes were statistically or clinically insignificant. The study had a placebo response rate of 55.6% - high placebo response rates are associated with failure to separate from placebo. Based on our primary outcome measure, we could not confirm previous studies showing a therapeutic effect of adjunctive NAC treatment on acute bipolar depression. Further studies with larger samples are needed to elucidate if specific subgroups could benefit from adjunctive NAC treatment.