Toward Biomarker-Guided Treatment in Psychosis

• 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.