The effects of adjunctive N-Acetylcysteine and cognitive training on working memory performance in adolescents with recent-onset psychosis: randomized double-blind-controlled clinical trial

BACKGROUND

Early onset psychosis (EOP), defined as the onset of psychotic symptoms before age 18, is associated with persistent cognitive deficits that negatively affect long-term clinical and functional outcomes. Among these impairments, working memory (WM) deficits are particularly relevant due to their association with poorer academic performance, impaired social functioning, and reduced quality of life. Cognitive dysfunction often persists despite symptom stabilization with antipsychotic treatment, highlighting the need for interventions specifically targeting cognition during adolescence, a critical neurodevelopmental period.

Although no pharmacological treatments have consistently demonstrated efficacy for cognitive deficits in EOP, cognitive training (CT) has emerged as a promising intervention capable of enhancing neuroplasticity and functional connectivity through repeated cognitive exercises. Similarly, N-acetylcysteine (NAC), a glutathione precursor with antioxidant and glutamatergic modulatory properties, has shown potential benefits in psychosis-related cognitive dysfunction. Evidence from schizophrenia-spectrum disorders suggests that NAC may reduce oxidative stress and neuroinflammatory processes linked to cognitive impairment and altered neurodevelopment. Combining NAC and CT may therefore produce synergistic effects by integrating neurobiological protection with targeted cognitive stimulation, potentially improving WM performance and broader cognitive functioning in adolescents with EOP.

METHODS

This randomized, double-blind, placebo-controlled clinical trial included adolescents with recent onset psychosis (n=30, aged 12–18 years) and evaluated the combined effects of NAC and CT on WM and global cognition over a 24-week intervention period. Participants were randomized into four groups: NAC+CT, NAC alone, placebo+CT, and placebo alone.

NAC was administered at a total dose of 3000 mg/day. The CT intervention consisted of a remotely delivered computerized protocol involving 20–40 hours of training distributed in 15-minute sessions targeting WM and executive functioning through adaptive cognitive exercises. Outcomes included baseline and endpoint assessments using the MATRICS Consensus Cognitive Battery (MCCB), as well as longitudinal WM performance measures obtained through the CT platform. Statistical analyses included independent t tests, two-way ANOVAs, and regression models examining longitudinal cognitive trajectories throughout the intervention period.

RESULTS

CT demonstrated significant main effects on WM performance (F(1,26)=6.07, p=.021, η²=0.189), particularly visuospatial WM measured with the WMS-III (F(1,26)=13.53, p=.001, η²=0.342). Significant improvements were also observed in global cognition measured with the MCCB composite score (F(1,26)=6.77, p=.015, η²=0.207). NAC did not show significant independent effects on cognition, although a trend-level interaction with CT was observed for global cognitive outcomes. Longitudinal scores obtained through the CT platform showed non-significant changes over time, possibly related to sample size and adherence variability.

CONCLUSIONS

CT significantly improved WM performance, particularly visuospatial WM, and overall cognition in adolescents with EOP, independently of NAC administration. Although NAC did not produce measurable cognitive benefits in this sample, preliminary findings suggest possible additive effects when combined with CT. Future research should explore individualized interventions and multimodal biomarkers to better understand treatment response and determine whether combined approaches can modify abnormal neurodevelopmental trajectories associated with psychosis and improve long-term functional outcomes.

References

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