Trial record 1 of 56 for:    stanley | United States, Indiana
Previous Study | Return to List | Next Study

The Effect of N-Acetyl Cysteine on Cortical Erosion in Early Stage Schizophrenia (Breier-Stanley)

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 by Indiana University
Sponsor:
Collaborators:
Stanley Medical Research Institute
Indiana University School of Medicine
The Brain Research Foundation
Information provided by (Responsible Party):
Nikki Mehdiyoun, Indiana University
ClinicalTrials.gov Identifier:
NCT01339858
First received: April 19, 2011
Last updated: July 30, 2014
Last verified: July 2014
  Purpose

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.


Condition Intervention Phase
Schizophrenia
Psychotic Disorder NOS
Schizoaffective Disorder
Schizophreniform
Drug: N-Acetyl Cysteine
Other: sugar pill
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver)
Primary Purpose: Treatment

Resource links provided by NLM:


Further study details as provided by Indiana University:

Primary Outcome Measures:
  • Cortical erosion [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    We anticipate that 12 months treatment with NAC as an add-on treatment will show significantly less cortical erosion as measured by cortical thickness, cortical volume and cortical white matter density (assessed by Diffusion Tensor Imaging [DTI]) than treatment with placebo


Secondary Outcome Measures:
  • working memory and semantic memory tasks as measure by fMRI [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    determine if 12 months of NAC add-on treatment is superior to placebo for fMRI determined working memory and semantic memory tasks as measured by fMRI

  • glutathione, N-acetylaspartate, and glutamine/glutamate levels [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    We anticipate that 12 months treatment with NAC as an add-on treatment will show significantly less reduction in glutathione, N-acetylaspartate, and glutamine/glutamate levels as compared to placebo as measured by cortical MR spectroscopy measures

  • attention measures [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    determine if 12 months of NAC add-on treatment is superior to placebo for attention measures (e.g., mismatch negativity, P300) as measured by electrophysiology methods. Electrophysiology measures will be recorded from a 64 channel, silver/silver-chloride scalp electrode montage.

  • Symptoms of a psychotic disorder [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    determine if 12 months of NAC add-on treatment is superior to placebo for symptom management of a psychotic disorder as assessed by the Positive and Negative Syndrome Scale (PANSS) and the Clinical Global Impressions Severity Scale (CGI-S)

  • cognitive functioning [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    determine if 12 months of NAC add-on treatment is superior to placebo for cognitive functioning as measured by the Brief Assessment of Cognition in Schizophrenia (BACS)

  • functional status [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    determine if 12 months of NAC add-on treatment is superior to placebo for functional measures and as measured by the Quality of Life (EuroQuoL)and the Personal and Social Performance Scale (PSP)

  • Safety [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
    spontaneously reported adverse events, Barnes Akathisia Scale,Simpson-Angus Scale, and medical evaluations including: Physical exam, vital signs, weight, waist circumference, pregnancy tests, and other laboratory measures of metabolic status


Estimated Enrollment: 60
Study Start Date: May 2011
Estimated Study Completion Date: June 2016
Estimated Primary Completion Date: June 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 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.
Drug: 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: Sugar Pill
matched placebo
Other: sugar pill
matched placebo will be supplied in unmarked capsules. Dosing regimen will be the same as in the N-Acetyl Cysteine arm.

Detailed 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.

  Eligibility

Ages Eligible for Study:   16 Years to 35 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01339858

Locations
United States, Indiana
Indiana University Psychotic Disorders Clinic Recruiting
Indianapolis, Indiana, United States, 46222
Contact: Nicole F Mehdiyoun, MA, CCRP    317-941-4287    nmehdiyo@iupui.edu   
Contact: Alan F Breier, MD    3179414167    abreier@iupui.edu   
Sub-Investigator: Nicole F Mehdiyoun, MA, CCRP         
Principal Investigator: Alan F Breier, MD         
Sub-Investigator: Alexander J Radnovich, MD, PhD         
Sub-Investigator: Emily Liffick, MD         
Sub-Investigator: Frederick Malloy, MS         
Sub-Investigator: Brian O'Donnell, PhD         
Sub-Investigator: William Hetrick, PhD         
Sub-Investigator: Natalie Case, MS         
Sub-Investigator: Amanda Bolbecker, PhD         
Sub-Investigator: Megan Gaunnac, BS         
Sub-Investigator: Jenifer Vohs, PhD         
Sub-Investigator: Josselyn Howell, BS         
Sub-Investigator: Teresa Kulig, MS         
Sub-Investigator: Brenna McDonald, PsyD         
Sub-Investigator: Tom Hummer, PhD         
Sub-Investigator: Carol Ott, PharmD         
Sub-Investigator: Amanda Roebel, MS         
Sub-Investigator: Steven Lindgren, BS         
Sub-Investigator: Amy Visco, BS         
Sub-Investigator: Matthew Yung, BS         
Sub-Investigator: Emily Good, MS         
Prevention and Recovery Center for Early Psychosis (PARC) Recruiting
Indianapolis, Indiana, United States, 46202
Contact: Nicole F Mehdiyoun, MA, CCRP    317-630-6046    nmehdiyo@iupui.edu   
Contact: Alan F Breier, MD    3179414287    abreier@iupui.edu   
Sub-Investigator: Michael Francis, MD         
Sub-Investigator: Carol Ott, PharmD         
Sub-Investigator: Andrew Saykin, PsyD         
Sub-Investigator: Joan Showalter, MA         
Sub-Investigator: David Spradley, RN         
Sub-Investigator: Emmalee Metzler, BA         
Sub-Investigator: Lindsay Joy, BA         
Sponsors and Collaborators
Indiana University
Stanley Medical Research Institute
Indiana University School of Medicine
The Brain Research Foundation
  More Information

Additional Information:
No publications provided

Responsible Party: Nikki Mehdiyoun, Clinical Research Coordinator to the Principal Investigator, Indiana University
ClinicalTrials.gov Identifier: NCT01339858     History of Changes
Other Study ID Numbers: 1008-12
Study First Received: April 19, 2011
Last Updated: July 30, 2014
Health Authority: United States: Institutional Review Board

Additional relevant MeSH terms:
Psychotic Disorders
Mental Disorders
Schizophrenia
Schizophrenia and Disorders with Psychotic Features
Acetylcysteine
N-monoacetylcystine
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Expectorants
Respiratory System Agents
Free Radical Scavengers
Antioxidants
Molecular Mechanisms of Pharmacological Action
Protective Agents
Physiological Effects of Drugs
Antidotes

ClinicalTrials.gov processed this record on August 26, 2014