N-acetylcysteine in a Double-Blind Randomized Placebo-Controlled Trial: Toward Biomarker-Guided Treatment in Early Psychosis

Abstract

Biomarker-guided treatments are needed in psychiatry, and previous data suggest oxidative stress may be a target in schizophrenia. A previous add-on trial with the antioxidant N-acetylcysteine (NAC) led to negative symptom reductions in chronic patients. We aim to study NAC’s impact on symptoms and neurocognition in early psychosis (EP) and to explore whether glutathione (GSH)/redox markers could represent valid biomarkers to guide treatment. In a double-blind, randomized, placebo-controlled trial in 63 EP patients, we assessed the effect of NAC supplementation (2700 mg/day, 6 months) on PANSS, neurocognition, and redox markers (brain GSH [GSHmPFC], blood cells GSH levels [GSHBC], GSH peroxidase activity [GPxBC]). No changes in negative or positive symptoms or functional outcome were observed with NAC, but significant improvements were found in favor of NAC on neurocognition (processing speed). NAC also led to increases of GSHmPFC by 23% (P = .005) and GSHBC by 19% (P = .05). In patients with high-baseline GPxBC compared to low-baseline GPxBC, subgroup explorations revealed a link between changes of positive symptoms and changes of redox status with NAC. In conclusion, NAC supplementation in a limited sample of EP patients did not improve negative symptoms, which were at modest baseline levels. However, NAC led to some neurocognitive improvements and an increase in brain GSH levels, indicating good target engagement. Blood GPx activity, a redox peripheral index associated with brain GSH levels, could help identify a subgroup of patients who improve their positive symptoms with NAC. Thus, future trials with antioxidants in EP should consider biomarker-guided treatment.

Adjunctive nutrients in first‐episode psychosis: A systematic review of efficacy, tolerability and neurobiological mechanisms

“…Furthermore, feasibility data indicated high tolerability, as retention was consistently high and adherence was >80%. Both of the trials of taurine (O'Donnell et al, 2016) and NAC (Conus et al, 2017) also reported that there were no adverse side-effects from either of these amino acids in FEP. Similarly, adjunctive treatment with antioxidant vitamins (C and E) did not result in any adverse events or side-effects (Dakhale et al, 2005;Eranti et al, 1998).…”

Glutamate hypothesis in schizophrenia

“…Furthermore, one RCT reported efficacy not only with negative and cognitive symptoms but also with positive symptoms in chronic schizophrenia . Moreover, a recent RCT demonstrated continuous effects of adjunctive NAC approach in long‐term treatment and effects in early psychosis . A recent meta‐analysis from 6 RCT showed that adjunctive NAC appears to have efficacy for schizophrenia …”

Early treatment response in first episode psychosis: a 7-T magnetic resonance spectroscopic study of glutathione and glutamate

“…Preliminary results have demonstrated that NAC, a GSH precursor, may be beneficial in psychotic disorders [69]. NAC has been shown to be efficacious in reducing the symptom burden [70], especially negative [71] and cognitive symptoms [72], and has the potential to alleviate treatment resistance in schizophrenia [73].…”

“…Our results suggest that treatments such as NAC may be efficacious particularly in patients who demonstrate an early poor response to antipsychotic medication, as they are likely to have a lower ability to synthesize GSH in response to glutamatergic excess. While MRS indices are indirect measures of tissue metabolite concentrations [74], given the evidence that oral NAC administration in patients with schizophrenia increases GSH content in the ACC [69], we consider MRS as a viable tool for translational investigations into the redox abnormalities of schizophrenia. More speculatively, we suggest that the association of ACC GSH levels at baseline and eventual clozapine-eligibility would be worth investigating in the future, given the lack of objective predictors of clozapine requirement in schizophrenia.…”