Cannabis, a Significant Risk Factor for Violent Behavior in the Early Phase Psychosis. Two Patterns of Interaction of Factors Increase the Risk of Violent Behavior: Cannabis Use Disorder and Impulsivity; Cannabis Use Disorder, Lack of Insight and Treatment Adherence.

Background: Previous literature suggests that prevalence of cannabis use in the early phase of psychosis is high, and that early psychosis patients are at high-risk for violent behavior. However, the link between cannabis use and violent behavior in early psychosis patients is unclear. We carried out a study on a sample of early psychosis patients, in order to explore the impact of cannabis use on the risk of violent behavior (VB), while taking into account (1) potential confounding factors and, (2) interactions with other dynamic risk factors of VB. Method: In a sample of 265 early psychosis patients, treated at the Treatment and Early Intervention in Psychosis Program (TIPP) in Lausanne, we used logistic regression models to explore the link between various dynamic risk factors of VB [positive symptoms, substance use disorder (drugs including cannabis, alcohol and others drugs), insight, impulsivity, affective instability, and treatment adherence], and VB occurring during treatment. In order to understand hierarchical effects attributable to the combinations of risk factors on VB we conducted a Classification and Regression Tree (CART). Results: Our results show that cannabis use disorder is a risk factor for VB. The associations among risk factors suggest the presence of two patient profiles with an increased rate of VB: the first is composed of patients with cannabis use disorder and impulsivity, and the second of patients combining cannabis use disorder, absence of insight and non-adherence to treatment. The results also show the moderating role of insight and adherence to treatment on the rate of VB in patients with cannabis use disorder. Conclusion: This study suggests that cannabis use disorder is a significant risk factor for VB amongst early psychosis patients, particularly when combined with either impulsivity, lack of insight and non-adherence to treatment. These results suggest that preventive strategies could be developed on the basis of such patient profiles.

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

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.

Treatment in early psychosis with N-acetyl-cysteine for 6months improves low-level auditory processing: Pilot study.

Sensory impairments constitute core dysfunctions in schizophrenia. In the auditory modality, impaired mismatch negativity (MMN) has been observed in chronic schizophrenia and may reflect N-methyl-d-aspartate (NMDA) hypo-function, consistent with models of schizophrenia based on oxidative stress. Moreover, a recent study demonstrated deficits in the N100 component of the auditory evoked potential (AEP) in early psychosis patients. Previous work has shown that add-on administration of the glutathione precursor N-acetyl-cysteine (NAC) improves the MMN and clinical symptoms in chronic schizophrenia. To date, it remains unknown whether NAC also improves general low-level auditory processing and if its efficacy would extend to early-phase psychosis. We addressed these issues with a randomized, double-blind study of a small sample (N=15) of early psychosis (EP) patients and 18 healthy controls from whom AEPs were recorded during an active, auditory oddball task. Patients were recorded twice: once prior to NAC/placebo administration and once after six months of treatment. The N100 component was significantly smaller in patients before NAC administration versus controls. Critically, NAC administration improved this AEP deficit. Source estimations revealed increased activity in the left temporo-parietal lobe in patients after NAC administration. Overall, the data from this pilot study, which call for replication in a larger sample, indicate that NAC improves low-level auditory processing in early psychosis.