Clinical trial NCT05142735: Effects of NAC on Symptoms of CHR Patients
Official title: Effects of N-acetylcysteine on Psychosis-like Symptoms and a Neurophysiological Biomarker of the Clinical High Risk for Schizophrenia
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Prodromal Schizophrenia
Keywords: psychosis
schizophrenia
N-acetylcysteine
prodrome
mismatch negativity
event-related potentials
clinical high risk state
Lead sponsor: Centre for Addiction and Mental Health
Sponsor class: OTHER
First posted: 2021-12-03
Enrollment: 90
Sex: ALL
Minimum age (years): 16
Maximum age (years): 35
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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.
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion Criteria:

1. meeting Criteria of Psychosis-Risk Syndromes (COPS) criteria on the Structured Interview for Psychosis-Risk Syndromes (SIPS)
2. capacity to provide informed consent
3. 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:

1. 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)
2. concomitant or past neurological condition
3. visual impairment which is not corrected to normal by prescription glasses history of reading disability
4. past antipsychotic treatment at a therapeutic dose
5. current treatment with a psychotropic medication except antidepressants on which the participants has been on a stable dose for at least 30 days.
6. pregnancy (as identified on self-report and/or rapid urine pregnancy test) or intent to become pregnant according to self-report
7. breastfeeding or plan to do so
8. history of kidney stones
9. current treatment with an antibiotic
10. current treatment with nitroglycerin
11. allergy to any ingredients in either the investigational product or placebo product

Primary outcomes:
measure: Change in positive psychosis-like symptoms from baseline to 8 weeks
timeFrame: Week 0 to week 8
Secondary outcomes:
measure: Change in mismatch negativity (MMN) amplitude from baseline to 8 weeks
timeFrame: Week 0 to week 8
measure: Change in N400 semantic priming effect from baseline to 8 weeks
timeFrame: Week 0 to week 8
Other outcomes:
Locations:
city: Toronto
country: Canada
facility: Centre for Addiction and Mental Health
state: Ontario
Study officials:
affiliation: Centre for Addiction and Mental Health
name: Michael Kiang, MD, PhD
role: PRINCIPAL_INVESTIGATOR
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