N-Acetylcysteine (NAC) in Schizophrenia Resistant to Clozapine: A Double-Blind, Randomized, Placebo-Controlled Trial Targeting Negative Symptoms

Abstract

Background and Hypothesis Clozapine is the most effective antipsychotic for treatment-resistant schizophrenia, yet a significant proportion of individuals on clozapine continue to experience disabling symptoms, despite being treated with an adequate dose. There is a need for adjunct treatments to augment clozapine, notably for negative and cognitive symptoms. One such potential agent is the glutathione precursor N-acetylcysteine (NAC). Study Design A randomized double-blind, multi-center, placebo-controlled trial for clozapine patients with enduring psychotic symptoms (n = 84) was undertaken to investigate the efficacy of adjunctive NAC (2 g daily) for negative symptoms, cognition and quality of life (QoL). Efficacy was assessed at 8, 24, and 52 weeks. Study Results NAC did not significantly improve negative symptoms (P = .62), overall cognition (P = .71) or quality of life (Manchester quality of life: P = .11; Assessment of quality of life: P = .57) at any time point over a 1-year period of treatment. There were no differences in reported side effects between the groups (P = .26). Conclusions NAC did not significantly improve schizophrenia symptoms, cognition, or quality of life in treatment-resistant patients taking clozapine. This trial was registered with “Australian and New Zealand Clinical Trials” on the 30 May, 2016 (Registration Number: ACTRN12615001273572).

Efficacy and acceptability of adjunctive n‐acetylcysteine for psychotic disorders: Systematic review and meta‐analysis

“…These findings were consistent withYolland et al (2020) at the ≤24 weeks mark, but after 24 weeks, Yolland et al observed significant improvement in negative symptoms and PANSS total scores with NAC treatment. Our study, which included a 52-week RCT(Neill et al, 2022) comparing the efficacy of 2 g/d NAC and placebo in 84 patients with clozapine-refractory schizophrenia, produced opposing results. Clozapine-refractory schizophrenia was defined as patients who had received at least three different chemical classes of antipsychotics and at least F I G U R E 3 Meta-analysis of N-acetylcysteine versus placebo for patients with psychotic disorder: total score as measured by the positive and negative syndrome scale (PANSS).…”

“…NAC was used as an adjunct therapy to antipsychotics (clozapine (Neill et al, 2022), risperidone (Farokhnia et al, 2013;Zhang et al, 2015)) in all studies. One study included treatment-resistant patients taking clozapine (Neill et al, 2022). The duration of the study ranged from 8 to 52 weeks, with four RCTs lasting 8 weeks, one 12 weeks, one method and were judged as low risk of bias, three trials were judged as unclear risk of bias because they did not report the random method clearly.…”

Schizophrenia Synaptic Pathology and Antipsychotic Treatment in the Framework of Oxidative and Mitochondrial Dysfunction: Translational Highlights for the Clinics and Treatment

“…The effect on disorganized thought is relevant in prognostic terms since disorganization domain scores may be predictors of treatment-resistant schizophrenia [ 317 ]. In a placebo-controlled RCT for TRS patients with persistent psychotic symptoms treated with clozapine, NAC as adjuvant therapy was not shown to significantly improve cognitive symptoms or quality of life in TRS patients [ 318 ]. Furthermore, a recent meta-analysis inferred that the recommendation in routine clinical practice for NAC treatment in schizophrenia might be premature despite its antioxidant potential.…”

Antipsychotic Augmentation With N-Acetylcysteine for Patients With Schizophrenia

“…Neill et al 11 described an investigator-initiated, industryindependent, moderately large (n = 84), well-designed, well-conducted, well-analyzed, 52-week RCT of NAC (2 g/d) in schizophrenia patients with persistent symptoms that were refractory to at least 3 classes of antipsychotic drugs as well as to ≥ 6 months of treatment with their current medication, clozapine. The study was conducted in medical centers in 4 cities in Australia.…”