Effects of NAC on Symptoms of CHR Patients

Study Overview
=================
Brief Summary
-----------------
Schizophrenia is a chronic debilitating psychotic disorder. Identifying persons with clinical high-risk (CHR) symptoms, which are like those of schizophrenia but less severe, and providing psychiatric care to these individuals has been shown to help prevent psychosis. Current medications used for CHR symptoms, however, are associated with substantial side effect burden. Therefore, practice guidelines do not recommend current medications as routine treatment for the CHR state, and there is a need to identify new treatments for this condition. Research suggests that abnormal brain oxidative stress may contribute to schizophrenia, offering a potential novel treatment target in the CHR state. Oxidative stress is an excess of free radicals, which are generated from normal metabolism and environmental exposures, and can damage cells. Antioxidants in the body normally neutralize free radicals. Antioxidant deficiency could result in excess oxidative stress that damages brain cells, leading to schizophrenia. Recent studies suggest that N-acetylcysteine (NAC), a precursor of the most abundant brain antioxidant, glutathione, may be a safe, well-tolerated treatment for schizophrenia. In light of this, NAC may also reduce symptoms and brain abnormalities in CHR patients.

Detailed Description
-----------------
The primary aim is to examine the effect of NAC on psychosis-like symptoms in CHR patients. Secondary aims are to examine the effect of NAC, in these patients, on the amplitude of the mismatch negativity (MMN), an electroencephalographic event-related potential (ERP) response to rare sounds among frequent ones; and the amplitude of the N400 semantic priming effect, an ERP response to unexpected compared to expected meaningful stimuli (e.g., words, pictures); both of which have been found to be reduced in both schizophrenia and the CHR state. This will be a randomized, double-blind, placebo-controlled trial. Ninety CHR patients will take either NAC 2000 mg orally or placebo, daily for 8 weeks. Psychosis-like symptoms will be assessed at baseline, week 4 and week 8 using the Positive symptom score of the Scale of Psychosis-Risk Symptoms in the Structured Interview for Psychosis-Risk Syndromes. MMN amplitude and the N400 semantic priming effect will be measured at baseline and week 8. We hypothesize that patients will have more improvement in psychosis-like symptoms, and greater increases in MMN amplitudes and N400 semantic priming effects, after taking NAC vs. placebo. If we find that NAC improves psychosis-like symptoms and/or these neurophysiological biomarkers of the CHR state, this would support further research on NAC as a preventive treatment against psychosis.

Official Title
-----------------
Effects of N-acetylcysteine on Psychosis-like Symptoms and a Neurophysiological Biomarker of the Clinical High Risk for Schizophrenia

Conditions
-----------------
Prodromal Schizophrenia

Intervention / Treatment
-----------------
* Dietary Supplement: N-Acetylcysteine
* Dietary Supplement: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: meeting Criteria of Psychosis-Risk Syndromes (COPS) criteria on the Structured Interview for Psychosis-Risk Syndromes (SIPS) capacity to provide informed consent if female, participant is not of child-bearing potential, defined as females who have undergone a sterilization procedure or have been post-menopausal for at least 1 year prior to screening OR participant is of child-bearing potential and agrees to use a medically approved method of birth control for the duration of the study Exclusion Criteria: meeting criteria for any other DSM-5 diagnosis at the time of the study (except -personality disorder, nicotine use disorder, or other substance use disorder in full remission) concomitant or past neurological condition visual impairment which is not corrected to normal by prescription glasses history of reading disability past antipsychotic treatment at a therapeutic dose current treatment with a psychotropic medication pregnancy (as identified on self-report and/or rapid urine pregnancy test) or intent to become pregnant according to self-report breastfeeding or plan to do so history of kidney stones current treatment with an antibiotic current treatment with nitroglycerin allergy to any ingredients in either the investigational product or placebo product

Ages Eligible for Study
-----------------
Minimum Age: 16 Years
Maximum Age: 35 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Participants are assigned to one of NAC or placebo groups in parallel for the duration of the study. This will be a randomized, double-blind, placebo-controlled trial. Participants will be randomized to take either NAC 2000 mg or placebo, in the form of oral capsules, every morning for 8 weeks.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental<br>N-Acetylcysteine 2000 mg (4 x 500-mg tablets) orally every morning for 8 weeks | Dietary Supplement: N-Acetylcysteine<br>* 2000 mg (4 x 500-mg tablets) every morning<br>* Other names: NAC;|
| Placebo Comparator: Placebo Comparator<br>N-Acetylcysteine Placebo tablet matching N-Acetylcysteine orally every morning for 8 weeks | Dietary Supplement: Placebo<br>* 4 placebo tablets every morning<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in positive psychosis-like symptoms from baseline to 8 weeks | Measured by the Positive symptom score of the Scale of Psychosis-Risk Symptoms, where the minimum score is 0 and the maximum score is 30, and higher scores mean a worse outcome. | Week 0 to week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in mismatch negativity (MMN) amplitude from baseline to 8 weeks | MMN amplitude will be measured as mean voltage from 135-205 ms post-stimulus onset of the ERP waveform formed by subtracting the average for standard tones from the average for deviant tones. | Week 0 to week 8 | 
| Change in N400 semantic priming effect from baseline to 8 weeks | N400 semantic priming effect will be measured as mean voltage from 300-500 ms post-stimulus onset of the ERP waveform formed by subtracting the average for related stimuli from the average for unrelated stimuli. | Week 0 to week 8 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
psychosis, schizophrenia, N-acetylcysteine, prodrome, mismatch negativity, event-related potentials, clinical high risk state