The current pharmacotherapy of bipolar depression often presents limited efficacy and increased risk for adverse events. N-acetylcysteine (NAC) has been suggested as potentially effective and well-tolerated adjunctive treatment for bipolar disorder (BD).
This systematic review and meta-analysis aimed to examine the efficacy of N-acetylcysteine, as an adjunctive therapy, for treating bipolar depression.
PubMed, Cochrane Library, Scopus databases, and grey literature were searched for studies retrieval. Randomized controlled trials including patients with a diagnosed bipolar disorder and a current depressive episode were included in the analysis. The measured variables included symptoms, functioning, and quality of life scales. The mean change in Montgomery-Åsberg Depression Rating Scale (MADRS) was set as the primary outcome.
A total of five studies were included in the analysis. A significant improvement was not observed from the addition of NAC to standard therapy in symptomatology [MADRS (MD = -3.32; 95% CI = -12.79 to 6.16), Young Mania Rating Scale (MD = -0.7; 95% CI = -2.15 to 0.75), Bipolar Depression Rating Scale (MD = -3.19; 95% CI = -15.48 to 9.1), and Clinical Global Impression for severity (MD = -0.13; 95% CI = -0.33 to 0.08)], functioning, [Global Assessment of Functioning Scale (MD = 3.21; 95% CI = -12.55 to 18.97), Social and Occupational Functioning Assessment Scale (MD = 0.47; 95% CI = -4.60 to 5.53), or quality of life [Quality of Life Enjoyment and Satisfaction Questionnaire (MD = 2.27; 95% CI = -9.13 to 13.67)].
There is no evidence indicating that NAC has beneficial effects as an adjunctive treatment for bipolar depression. Future trials with improved methodological design and efficient sample sizes are required to draw safer conclusions.

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