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Is oxidative stress a therapeutic target in schizophrenia?
• All FDA-approved antipsychotics for schizophrenia antagonize dopamine D2 receptors
• Identification of novel treatment targets in schizophrenia is needed
• Recent studies suggest that oxidative stress (an imbalance of free radicals), particularly deficits in the glutathione (GSH) system, plays a role in the pathophysiology of schizophrenia
• Two randomized controlled trial (RCTs) found that adjunctive N-acetylcysteine (NAC), an antioxidant and GSH precursor, improved (particularly negative) symptoms in schizophrenia with modest effect sizes[1,2]
• Evidence from developmental rodent models of schizophrenia suggests that the adverse effects of oxidative stress may occur early in the illness trajectory
• Conus and colleagues[3] performed an RCT of adjunctive NAC in early psychosis
The aims of the present study were to determine the effect of adjunctive NAC on:
• Negative symptoms in early psychosis
• Positive and cognitive symptoms in early psychosis
• Brain GSH parameters, and whether response to NAC is associated with peripheral blood GSH-related biomarkers
• The authors performed a 6-month, double-blind, placebo-controlled, 2-center RCT of add-on NAC vs placebo in early psychosis from 2009-2014
• Inclusion criteria were age 18-40, psychotic disorder diagnosis (based on the Comprehensive Assessment of At Risk Mental States scale), < 12 months of treatment for psychosis, and sufficient clinical stability
• Subjects were randomized 1:1 to 2700 mg/d NAC (1800 mg qAM + 900 mg qPM) or placebo for 6 months
• Subjects were seen monthly for 6 months, and then at 1 month post-discontinuation, and assessed for psychopathology, cognition, psychosocial functioning, and medication adverse effects
• Blood GSH system markers and brain medial prefrontal cortex GSH (via 1H-MRS) were measured at multiple time points during the study
• 302 patients were screened, and 63 were randomized (32 to NAC and 31 to placebo)
• There were no significant between-group differences regarding baseline clinical and demographic characteristics
• Mean subject age was 25, 77% were male, and the majority of subjects were Caucasian
• There were no significant differences between groups on change in psychopathology or functional outcome
• NAC improved cognitive processing speed (verbal fluency and trail making test)
• Improved cognitive processing speed was correlated with decreased negative symptoms in NAC-treated patients
• NAC treatment was associated with a mean 19% increase in blood GSH levels, and a mean 23% increase in medial prefrontal cortex GSH levels
• High baseline blood GSH peroxidase activity was a predictor of decrease in PANSS positive subscale scores with NAC treatment
• Treatment with NAC was not associated with significant adverse effects
The authors concluded that in patients with early psychosis:
• The addition of NAC to standard treatment did not improve symptoms or functioning
• Oral NAC increased brain GSH levels and improved cognition (processing speed)
• Peripheral blood GSH peroxidase identified a response to NAC in terms of positive symptoms
• NAC administration modified peripheral blood markers of oxidative stress/redox status, which paralleled clinical improvement
• These peripheral blood markers also allowed identification of a subgroup of patients who benefited from NAC
• Findings represent an important step toward biomarker-guided treatment in psychosis
REFERENCES:
1. Berk M, Copolov D, Dean O, et al. N-acetyl cysteine as a glutathione precursor for schizophrenia-a double-blind, randomized, placebo-controlled trial. Biol Psychiatry. 2008;64:361-368.
2. Farokhnia M, Azarkolah A, Adinehfar F, et al. N-acetylcysteine as an adjunct to risperidone for treatment of negative symptoms in patients with chronic schizophrenia: a randomized, double-blind, placebo-controlled study. Clin Neuropharmacol. 2013;36:185-192.
3. Conus P, Seidman LJ, Fournier M. N-acetylcysteine in a double-blind randomized placebo-controlled trial: towards biomarker-guided treatment in early psychosis. Schizophr Bull. 2017. doi:10.1093/schbul/sbx093.