N-Acetyl-Cysteine (Nac) Intervention and Mitochondrial Mechanisms in- Early Psychosis Patients

Abstract Background Schizophrenia (SZ) is associated with neurocognitive dysfunction already in the early phase of the disease. However, cognitive impairments are actually poorly treated by pharmacological interventions, leaving severe problems in functioning (Green et al.. 2000). Redox dysregulation and oxidative stress emerge as a central pathological mechanism underlying schizophrenia (Cuenod et, 2023). Individuals with SZ show increased oxidative damage and reduced antioxidant capacity. Impairments of fast-spiking GABA parvalbumin interneurons (PVI), leading to cortical excitatory-inhibitory imbalance, underlie cognitive deficit. A variety of models relevant to SZ and psychotic disorders, converge on oxidative stress induced PVI integrity impairment as a common underlying pathway (Steullet &Cabungcal et al, 2017). In a proof-of-concept trial in patients with early psychosis (EPP), the antioxidant N-acetyl-cysteine (NAC) increased prefrontal glutathione levels in a small subgroup of patients, thus suggesting target engagement. NAC improved moderately processing speed (Conus et al., 2017) with no effect on other clinical symptoms. However in a subgroup of patients with high blood oxidative markers at baseline, NAC improved positive symptoms, in parallel with changes in peripheral redox status, (Conus et al., 2017). To search for biomarkers capturing circuitry dysfunction needed for patient stratification, we have identified a molecular mechanism linking mitochondria and oxidative stress induced PVI impairments. Oxidative stress upregulates the microRNA miR-137 in PVI, a gene strongly associated with SZ (Ripke et al., 2), leading to decreased COX6A2, a subunit of cytochrome c oxidase complex IV specific to PVI, and impaired mitophagy with mitochondrial damage accumulation (Khadimallah et al., 2022). In EPP, high miR-137 and low COX6A2 plasma exosomal biomarkers allow to select with high accuracy patients with worse psychopathological status and neurocognitive performance, and impaired global and social functioning. Aims & Objectives We now aim to compare the effect of NAC between subgroups of patients with and without mitochondria dysfunction. Method The study was a 6-month, double-blind, randomized, placebo-controlled trial of NAC supplementation (2700 mg/d) to standard medications. Sixty-one patients (31 NAC, 30 placebo) with a diagnostic of psychotic disorder and less than 12 months of antipsychotic treatment were enrolled. We assessed and compared in NAC and placebo groups at baseline and at the end of treatment: 1) Neurocognition using with the MATRICS Consensus Cognitive Battery (MCCB) (Nuechterlein et al., 2008). b) Global assessment of functioning (GAF), c) Brain-derived exosomal levels of miR-137 and COX6A2. Results Patients with high baseline plasma exosomal miR-137 levels in the NAC group showed significant improvements in processing speed, attention/vigilance, and GAF. The amelioration in processing speed within the NAC group was inversely correlated with exosomal miR-137 levels. Moreover, an improvement of GAF was positively linked to higher COX6A2 exosomal levels in both NAC and placebo groups. Discussion & Conclusions The addition of NAC significantly improved neurocognition and functional outcome in early psychosis patients, particularly in those with mitochondrial dysfunction, in parallel with associated biomarkers miR-137 and COX6A2. If replicated in larger studies, in particular with treatment focusing on mitochondrial mechanisms, our results would open the way for personalized and mechanistically guided treatments.