N-acetylcysteine as an adjunctive treatment for bipolar depression and major depressive disorder: a systematic review and meta-analysis of double-blind, randomized placebo-controlled trials

Kishi et al., 2020 | Psychopharmacology (Berl) | Meta Analysis

Citation

Kishi Taro, Miyake Nobumi, ... Iwata Nakao. N-acetylcysteine as an adjunctive treatment for bipolar depression and major depressive disorder: a systematic review and meta-analysis of double-blind, randomized placebo-controlled trials. Psychopharmacology (Berl). 2020-Nov;237(11):3481-3487. doi:10.1007/s00213-020-05629-2

Abstract

RATIONALE: It remains unclear whether using N-acetylcysteine as an adjunctive treatment has any benefit for bipolar depression and major depressive disorder. OBJECTIVES: A systematic review and random-effect meta-analysis of double-blind, randomized placebo-controlled trials was conducted to explore the clinical question. METHODS: Outcomes included improvement in depression scale scores (primary), Young Mania Rating Scale score, Hamilton Anxiety Rating Scale score, Clinical Global Impression-Severity Scale (CGI-S) score, Global Assessment of Functioning Scale score, Social and Occupational Functioning Assessment Scale score, Range of Impaired Functioning Tool score, Streamed Longitudinal Interval Clinical Evaluation for the Longitudinal Interview Follow-Up Evaluation score, quality of life scales scores, and the incidence of all-cause discontinuation and individual adverse events. RESULTS: Seven studies (n = 728, 8-24 weeks, mean age = 46.81, % female = 58.45%) were included. N-acetylcysteine did not improve depressive symptoms compared with placebo (N = 7, n = 579, standardized mean difference (SMD) = - 0.12, 95% confidence interval (95% CI) = - 0.38, 0.14, p = 0.38, I2 = 52.74%). The meta-regression analysis detected an association between effect size and publication year (coefficient = 0.06, 95% CI = 0.00, 0.11, p = 0.04, I2 = 27.56%). Although N-acetylcysteine was superior to placebo in CGI-S score (N = 6, n = 563, SMD = - 0.28, 95% CI = - 0.47, - 0.10, p < 0.01, I2 = 14.88%), there was no significant difference in the other efficacy outcomes between the treatment groups. Although N-acetylcysteine was associated with a higher incidence of gastrointestinal adverse events compared with placebo (N = 4, n = 537, risk ratio = 1.79, 95% CI = 1.37, 2.32, p < 0.01, I2 = 0.00%, number needed to treat to harm = 7), there was no significant difference in all-cause discontinuation and other safety outcomes between the treatments. CONCLUSIONS: Although N-acetylcysteine decreased CGI-S score, no specific improvements in symptoms were identified.

Key Findings

Seven studies (n = 728, 8-24 weeks, mean age = 46.81, % female = 58.45%) were included. N-acetylcysteine did not improve depressive symptoms compared with placebo (N = 7, n = 579, standardized mean difference (SMD) = - 0.12, 95% confidence interval (95% CI) = - 0.38, 0.14, p = 0.38, I2 = 52.74%). The meta-regression analysis detected an association between effect size and publication year (coefficient = 0.06, 95% CI = 0.00, 0.11, p = 0.04, I2 = 27.56%). Although N-acetylcysteine was superior to

Outcomes Measured

anxiety
depression

Population

Field	Value
Population	See abstract
Sample Size	728
Age Range	See abstract
Condition	anxiety

MeSH Terms

Acetylcysteine
Adult
Bipolar Disorder
Major Depressive Disorder
Double-Blind Method
Drug Therapy, Combination
Female
Free Radical Scavengers
Humans
Male
Middle Aged
Quality of Life
Randomized Controlled Trials as Topic
Treatment Outcome

Evidence Classification

Level: Meta Analysis
Publication Types: Journal Article, Meta-Analysis, Systematic Review
Vertical: NAC-mental

Provenance

PMID: 32767039
DOI: 10.1007/s00213-020-05629-2
PMCID: Not in PMC
Verified: 2026-04-09 via PubMed E-utilities API

Source extracted via PubMed E-utilities API on 2026-04-09