Meta-analysis of randomised controlled trials with N-acetylcysteine in the treatment of schizophrenia

Systematic review and meta-analysis of randomized controlled trials in people with schizophrenia or first-episode psychosis. Across 7 trials, 220 participants were randomized to NAC and 220 to placebo, with studies conducted in community settings in Australia, the United States, Switzerland, Iran, and China.

N-acetylcysteine (NAC) was used as an adjunct to standard antipsychotic treatment in randomized placebo-controlled trials. Daily doses ranged from 600 mg/day to 3600 mg/day, with treatment durations from 8 weeks to 52 weeks; most studies used 2000 mg/day, and some regimens were titrated.

Adjunctive NAC showed a modest overall benefit, with the clearest effects on negative symptoms and total PANSS scores after longer treatment durations. At 24 weeks or longer, PANSS negative symptoms improved versus placebo (SMD = -0.41, p = 0.006) and PANSS total scores improved (SMD = -0.64, p < 0.001); across final timepoints, PANSS negative symptoms also favored NAC (SMD = -0.72, p = 0.003) and PANSS general symptoms were borderline (SMD = -0.34, p = 0.05). NAC also improved working memory across three studies (SMD = 0.56, p = 0.005), while processing speed did not differ significantly (SMD = 0.27, p = 0.27). Benefits were not clear at shorter durations, so the overall conclusion is that NAC may help schizophrenia symptoms, especially negative symptoms, with possible cognitive benefit after longer treatment.

Interpretation is limited by heterogeneity across trials, relatively few studies, and variable reporting of demographics, safety, and secondary outcomes. Effects were inconsistent at shorter durations, and several outcomes were null or only borderline significant, reducing certainty about the magnitude and durability of benefit.