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.

Figures

Fig. 1.

CONSORT flow diagram, primary and secondary outcomes. (A) Reasons for withdrawal from trial, 1white matter lesions detected at baseline MRI scan; 2withdrew at baseline; 3lack of motivation; 4side effects. (B) Change in PANSS− score vs baseline in NAC (red circles) and placebo (green triangles) groups at each visit. (C) Comparison of NAC vs placebo in the rate of improvement. PANSS, Positive and Negative Syndrome Scale; GAF, General Assessment of Functioning; SOFAS, Social and Occupational Functioning Assessment Scale; β, an estimate of NAC effect vs placebo; SE, standard error.

Fig. 2.

Effect of NAC vs placebo on processing speed’s measures. Evolution of trail making test (A), verbal fluency (B), processing speed factor T-scores (C) in NAC (red circles), and placebo (green triangles) groups. (D) Statistical comparison between NAC and placebo groups; partial-eta-square ( ηp2 ) indicates the effect size. Linear correlations between changes in PANSS− and changes in processing speed factor (E) and verbal fluency T-scores (F) in NAC-treated patients.

Fig. 3.

Effect of NAC vs placebo on GSH levels. (A) Boxplot illustrating changes vs baseline in GSHBC after 2 and 6 months and after washout (7 months) of treatment with NAC (gray boxes) or placebo (white boxes). (B) GSHmPFC levels in patients with NAC (n = 12, red circles, left) or placebo (n = 12, green triangles, right).

Fig. 4.

Additional analysis by classification and regression tree. (A) Illustration of the classification based on GPxBC enzymatic activity in the NAC group: 36% of patients have an activity at baseline above 22.3 U/g of Hb associated with a mean decrease of PANSS+ score of −5.8 points; 64% of patients have an activity at baseline below 22.3 U/g of Hb associated with a mean improvement of PANSS+ score of −1.5 point. (B) Effect of NAC add-on treatment on PANSS+ scores on patients with baseline activity of GPxBC above 22.3 U/g of Hb. Values are coefficients of each factor in the linear model. SE, standard error. P-values under 0.1 are indicated in bold. (C) Evolution of PANSS+ scores vs baseline in patients with low (left) or high (right) basal activity of GPxBC in NAC (red circles) or placebo (green triangles) groups during the trial (1–6 months) and after washout (7 months). (D, E) Changes in PANSS+ scores vs baseline and changes in GPxBC activity vs baseline is illustrated by linear correlation in patients with basal activity of GPxBC above 22.3 U/g of Hb. Patients under NAC (left) or Placebo (right) at 2 (D) and 6 months (E). Dots depict individual values, gray zones 95% confidence intervals.