Overview

This trial is active, not recruiting.

Conditions schizophrenia, psychotic disorder nos, schizoaffective disorder, schizophreniform
Treatments n-acetyl cysteine, sugar pill
Phase phase 4
Sponsor Indiana University
Collaborator Stanley Medical Research Institute
Start date May 2011
End date December 2016
Trial size 60 participants
Trial identifier NCT01339858, 1008-12

Summary

The primary objective of this study is to determine if NAC, added to existing antipsychotic treatment, is superior to placebo for cortical erosion in patients with early stage psychosis. The primary hypothesis is that there will be significantly less cortical erosion as measured by cortical thickness, cortical volume and cortical white matter density (assessed by DTI) in patients treated for 12 months with NAC as compared to those treated with placebo. The secondary objectives of this study are to determine if 12 months of NAC add-on treatment is superior to placebo for fMRI determined working memory and semantic memory tasks, cortical MR spectroscopy measures (glutathione, N-acetylaspartate, and glutamine/glutamate levels), electrophysiologically determined attention measures (e.g., mismatch negativity, P300), symptoms, functional measures and cognitive functioning.

United States No locations recruiting
Other Countries No locations recruiting

Study Design

Allocation randomized
Intervention model parallel assignment
Masking double blind (subject, caregiver)
Primary purpose treatment
Arm
(Experimental)
NAC and matched placebo will be supplied in unmarked capsules. Each NAC capsule will contain 480 mg of NAC. Dosing will begin at 480 mg/d and titrated up by 480 mg/d each week until a maximum dose of 2880 mg/d (BID) is reached. This approximate dose was effective and well tolerated in a recent study of treatment refractory obsessive-compulsive disorder by Krystal and colleagues at Yale (16). In addition, a double-blind placebo controlled trial recently completed at IUSM Riley Hospital in children (age 4 to 12 years) with autism spectrum disorders used doses ranging from 900 mg/day to 4200 mg/day and reported no serious adverse events and found the agent well tolerated (15). Dose adjustments downward to 1920 mg/d will be permitted if tolerability issues are encountered at the maximum dose.
n-acetyl cysteine
NAC and matched placebo will be supplied in unmarked capsules. Each NAC capsule will contain 480 mg of NAC. Dosing will begin at 480 mg/d and titrated up by 480 mg/d each week until a maximum dose of 2880 mg/d (BID) is reached. This approximate dose was effective and well tolerated in a recent study of treatment refractory obsessive-compulsive disorder by Krystal and colleagues at Yale (16). In addition, a double-blind placebo controlled trial recently completed at IUSM Riley Hospital in children (age 4 to 12 years) with autism spectrum disorders used doses ranging from 900 mg/day to 4200 mg/day and reported no serious adverse events and found the agent well tolerated (15). Dose adjustments downward to 1920 mg/d will be permitted if tolerability issues are encountered at the maximum dose
(Placebo Comparator)
matched placebo
sugar pill
matched placebo will be supplied in unmarked capsules. Dosing regimen will be the same as in the N-Acetyl Cysteine arm.

Primary Outcomes

Measure
Cortical erosion
time frame: 12 months

Secondary Outcomes

Measure
working memory and semantic memory tasks as measure by fMRI
time frame: 12 months
glutathione, N-acetylaspartate, and glutamine/glutamate levels
time frame: 12 months
attention measures
time frame: 12 months
Symptoms of a psychotic disorder
time frame: 12 months
cognitive functioning
time frame: 12 months
functional status
time frame: 12 months
Safety
time frame: 12 months

Eligibility Criteria

Male or female participants from 16 years up to 35 years old.

SUBJECTS DIAGNOSED WITH A PSYCHOTIC DISORDER Inclusion Criteria: - Patients with a DSM-IV diagnosis of schizophrenia, schizophreniform, schizoaffective, psychosis disorder NOS - Age range 16-35 years - Male or female - Within 2 years of the first onset of psychotic symptoms that resulted in work/school/social dysfunction and/or treatment (PI will review potential subjects who have been experiencing symptoms >2 years but <5 years and will allow to enter the trial on a case-by-case basis) - Ability to provide informed consent and/or assent (all subjects) - For subjects 16 and 17 years of age, parental/guardian consent Exclusion Criteria: - Unstable medical conditions - Active seizure disorder - Pregnant or lactating women - Females unwilling to utilize birth control - Implanted pacemaker, medication pump, vagal stimulator, deep brain stimulator, TENS unit, or ventriculoperitoneal shunt (because of MR studies). - Known IQ less than 70 - DSM-IV-TR diagnosis of substance dependence (with the exception of nicotine or caffeine dependence) - Psychotic symptoms secondary to substance use - Considered a high risk for suicidal acts - active suicidal ideation with intent to act as determined by clinical interview HEALTHY CONTROL SUBJECTS The comparison subjects will consist of 40 healthy normal volunteers recruited from the community who will be age and gender matched to subjects diagnosed with a psychotic disorder entering the NAC treatment study Inclusion Criteria: 1. Age range of 18-30 (inclusive) and able to give voluntary informed consent (Note: Subjects diagnosed with a psychotic disorder under the age of 18 will be age matched to control subjects aged 18). 2. Male or Female Exclusion Criteria: 1. Current severe mental disorder (Schizophrenia, schizophreniform disorder, other psychotic disorders, bipolar disorder, major depressive disorder) 2. Known/documented IQ < 70 3. Pregnant or lactating women 4. Acute, serious, or unstable medical condition 5. Metallic implants or other contraindication to MRI (including but not limited to: Implanted pacemaker, medication pump, vagal stimulator, deep brain stimulator, TENS unit, or ventriculoperitoneal shunt) 6. First degree relative with a psychotic disorder (i.e. schizophrenia, schizophreniform, schizoaffective, psychosis disorder NOS, substance induced psychosis, major depression with psychotic features, or bipolar disorder with psychotic features). 7. Current DSM-IV-TR diagnosis of substance abuse or dependence (with the exception of nicotine or caffeine) as diagnosed within the 6 months prior to screening visit 8. Known history of seizure disorder, head trauma, stroke, traumatic brain injury, significant loss of consciousness

Additional Information

Description Schizophrenia is a severe, debilitating illness that typically begins during the teen-age years and early twenties, and worsens over time as it evolves into a chronic, life-long disorder. Existing treatments suppress psychotic symptoms but do not prevent the evolution of underlying disease processes that results in poor, long term outcomes. Recent studies have shown that progressive erosion of cortical mass occurs during the early stages of schizophrenia (1-3). The investigators hypothesize that arresting cortical erosion during the early phases of schizophrenia will prevent subsequent clinical deterioration and the descending course of illness associated with this disorder. The investigators propose to establish a research program that will assess the ability of agents with neuroprotective properties to halt cortical loss and thereby prevent subsequent clinical deterioration. N-acetyl cysteine (NAC) is an attractive molecule for the proposed study because of two of its mechanistic properties. First, it is an established neuroprotective agent. NAC is a precursor to glutathione which is a primary detoxifier of reactive oxygen and other radical molecules which damage neuronal tissue (4-6). Glutathione deficiencies have been well documented in schizophrenia (7, 8). Second, NAC modulates glutamate release. NMDA hypofunction and altered glutamate release have been hypothesized to contribute to the cortical atrophy observed in early stage schizophrenia (9, 10). NAC has been shown to antagonize both the phencyclidine (PCP) effects of increased frontal glutamate levels and induction of social isolation in rodents (11). PCP is a pharmacological model of schizophrenia. In a controlled clinical trial of patients with chronic schizophrenia, NAC improved mismatch negativity, a pre-attentive measure of cortical information processing that has been consistently implicated in the pathophysiology of schizophrenia and has been shown to correlate with cortical erosion in early stage patients (12, 13). In a double-blind, placebo controlled clinical trial of chronic schizophrenic patients, NAC significantly improved general psychopathology scores, negative symptoms and extrapyramidal symptoms (14). NAC was well tolerated with no significant effects on any safety parameter or adverse events. The favorable tolerability of NAC has been further demonstrated in a recent study conducted at IUSM Riley Hospital in children (ages 4 to 12 years) with autism at relatively high doses (dose range of 900 to 4200 mg/day) in which there were no serious adverse events reported and NAC was well tolerated (15). The investigators propose to determine if NAC has disease modifying potential in early stage schizophrenia. The investigators hypothesize that NAC will improve measures of cortical integrity in early stage schizophrenia and these brain effects will be related to improvements in negative symptoms and cognitive functioning. Primary outcome measures in the trials will be serial assessments of cortical integrity using magnetic resonance structural (cortical thickness, cortical volume, diffuses tensor imaging, DTI). In addition the investigators will assess the possible effects of NAC treatment on other parameters linked to cortical erosion including fMRI coupled with working memory and semantic memory tasks, MR spectroscopy (cortical glutathione, N-acetylaspartate, and glutamine/glutamate levels) and electrophysiological measures (e.g., mismatch negativity, P300). The investigators will also determine the relationship between effects of NAC on negative symptoms, positive symptoms, functional status, cognition (BACS), and safety parameters; and brain indices.
Trial information was received from ClinicalTrials.gov and was last updated in August 2016.
Information provided to ClinicalTrials.gov by Indiana University.