N-acetylcysteine as an adjunctive treatment for bipolar depression: A systematic review and meta-analysis of randomized controlled trials

Objectives Previous studies and meta-analyses suggested that N-acetylcysteine (NAC) was superior to placebo in improving depression in bipolar disorder. However, more recent data, including two larger trials, found that NAC was no more effective than placebo. We conducted a meta-analysis to appraise the possible efficacy of NAC in treating bipolar depression. Methods A systematic review and meta-analysis of double-blind, placebo-controlled trials of NAC as a treatment augmentation strategy for bipolar depression was carried out in PubMed (1966-2020). We utilized random-effect analysis to evaluate improvement in depressive symptoms from baseline to endpoint as the primary efficacy measure. Results Six trials including 248 patients were included. Treatment augmentation with NAC showed a moderate effect size favoring NAC over placebo (d = 0.45, 95% C.I.: 0.06-0.84). There was substantial heterogeneity (I-2 = 49%). Meta-regression analyses did not identify any moderator that might explain variation in heterogeneity, including baseline depressive symptom scores, mean NAC dose, or duration of study. Conclusions Results from six clinical trials suggest that treatment augmentation with NAC for bipolar depression appears to be superior to placebo, with a moderate effect size, but a large confidence interval. Larger clinical trials, investigating possible moderating factors, such as NAC dose, treatment duration, baseline depression severity, or chronicity of illness, are warranted.