N-Acetyl-Cysteine (NAC) in Early Phase Schizophrenia Spectrum Psychosis (NACPSY)

Effects of Oral N-Acetyl-Cysteine (NAC) in the Early Phase of Schizophrenia Spectrum Psychosis: Randomized, Parallel, Double- Blind, Placebo Controlled Trial

The investigators seek to examine the effect of add-on N-Acetyl-Cysteine (NAC) in the early phase of schizophrenia spectrum illness in collaboration with researchers Kim Do, PhD, and Philippe Conus, MD in Switzerland. Modifications of brain structure are thought to occur during the pre-illness phase and around the transition to psychosis. Therefore, studying new treatments that could target changes occurring during this period is of critical importance.

Aims:

Does add-on NAC treatment in early psychosis influence:

• positive and negative symptoms
• extrapyramidal side-effects of other medication
• plasma concentration of glutathione
• Mismatch Negativity, a physiological marker

Study Overview

• Status: Completed
• Conditions: Schizophrenic Psychoses
• Intervention / Treatment: Drug: n-acetylcysteine; Drug: Placebo

Detailed Description

The study proposes that a glutathione deficit leading to an abnormal response to oxidative stress is a vulnerability factor, combined with other brain specific factors, in brain functioning of some individuals with schizophrenia (Do et al., 2010). N-acetyl-cysteine is hypothesized to cross the blood-brain barrier and increase glutathione in the brain.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
    • Boston, Massachusetts, United States, 02215
      • Massachusetts Mental Health Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 35 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Capacity to provide informed consent
• DSM IV TR diagnosis of schizophrenia, schizophreniform, schizoaffective
• Psychiatric and medical stability
• Prescribing clinician's premission to participate, assurance of medical stability
• Having met threshold criteria for psychosis on CAARMS (Comprehensive Assessment of at Risk Mental States Scale) Psychosis subscale
• Up to 12 months of antipsychotic treatment

Exclusion Criteria:

• Severe medical comorbidities
• Previous cerebral trauma
• Substance induced psychosis or organic psychosis
• Mental retardation
• NAC allergy
• Pregnancy, females and males planning pregnancy
• Treatment with antioxidants
• Insufficient command of English

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: n-acetyl-cysteine; N-Acetyl cysteine effervescent tablets in water 2 in am and 1 in pm for 28 weeks	Drug: n-acetylcysteine; 900 mg effervescent PharmaNAC tablet in water or juice: two tablets in the AM, one tablet in PM; Other Names: PharmaNAC
Placebo Comparator: Placebo; matching effervescent tablets in water 2 in am and 1 in pm	Drug: Placebo; Placebo tablets are placed in water or juice in the AM and PM

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Negative Symptoms of Schizophrenia as Measured on the PANSS	Positive and Negative Symptom Scale was used to assess psychopathology. The sum of items N1 - N7 including N1) blunted affect, N2) emotional withdrawal, N3) poor rapport, N4) passive apathetic social withdrawal, N5) difficulty in abstract thinking, N6) lack of spontaneity and flow of conversation, and N7) sterotyped thinking were used to analyze negative symptoms of schizophrenia and were assessed for the previous week: RATING SCALE 1: Absent 2: Minimal 3: Mild 4: Moderate 5: Moderate Severe 6: Severe 7: Extreme The higher the score the worse the symptoms. The lowest possible score is 7 and the highest possible score is 49 .	at 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Positive Symptoms (PANSS)	Positive and Negative Symptom Scale was used to assess psychopathology. The Positive symptom subscale of schizophrenia includes the sum of items P1 -P7 including P1) Delusions, P2) conceptual Disorganization, P3) Hallunicatory Behavior, P4) Excitement, P5) Grandiosity, P6) Suspiciousness and Persecution, and P7) Hostility and were assessed for the previous week: RATING SCALE 1: Absent 2: Minimal 3: Mild 4: Moderate 5: Moderate Severe 6: Severe 7: Extreme The higher the score the worse the symptoms. The lowest possible score is 7 and the highest possible score is 49 .	at 6 months
Global Assessment of Functioning (GAF)	Measure Description: Clinical Measure of Global level of Symptoms (Sx) and Functioning from 1 (Worst) to 100 (Best) in groups of 10: 100 - 91: Superior functioning 90 - 81: Absent or minimal Sx 80 - 71: If symptoms are present and expected 70 - 61:Some mild Sx 60 - 51: Moderate Sx 50 - 41: Serious Sx 40 - 31: Some impairment in reality testing or communication 30 - 21: Behavior is considerably influenced by delusions or hallucinations 20 - 11: Some danger of hurting self or others 10 - 1: Persistent danger of severely hurting self or others	at 6 months
Social and Occupational Functioning Assessment Scale (SOFAS)	Measure of social and occupational functioning using the Social and Occupational Functioning Assessment Scale Measure Description: Rating of Overall Social and Occupational Functioning on a scale of 1 (worst) to 100 (best) in groups of 10: 100-91: Superior functioning 90-81: Good functioning 80-71: Slight impairment 70-61: Some difficulty 60-51: Moderate difficulty 50-41: Serious impairment 40-31: Major impairment 30-21: Inability to function in almost all areas 20-11: Unable to function independently 10-1: Unable to function without harming self or others	at 6 months
Change in Cognition and Working Memory (MATRICS) Speed of Processing	The MATRICS is neurocognitive battery designed to assess cognition. Processing speed is a composite score including the following tests: Trail Making Test, BACS: Symbol Coding, Category Fluency: Animal Naming. The score is a standardized T-Score which indicates the number of standard deviations above or below the mean, a T-Score of 50, in 10 point increments. A T-Score of 60 indicates 1 standard deviation above the mean and a T-Score of 40 indicates 1 standard deviation below the mean. A score below 50 indicated cognitive processing below that of an age and gender matched healthy control population. A score above 50 indicates cognitive processing above that of an age and gender matched healthy control population.	at 6 months
Change in Cognition and Working Memory (MATRICS) Working Memory	The MATRICS is neurocognitive battery designed to assess cognition. Working Memory score is a composite score based on the following sub-test WMS-III Spatial Span and Letter-Number Span. The score is a standardized T-Score which indicates the number of standard deviations above or below the mean, a T-Score of 50, in 10 point increments. A T-Score of 60 indicates 1 standard deviation above the mean and a T-Score of 40 indicates 1 standard deviation below the mean. A score below 50 indicated cognitive processing below that of an age and gender matched healthy control population. A score above 50 indicates cognitive processing above that of an age and gender matched healthy control population.	at 6 months
Change in Cognition and Working Memory (MATRICS) Attention and Vigilance	The MATRICS is neurocognitive battery designed to assess cognition. Sustained attention and Vigilance is a composite score based on the Continuous Performance Test -Identical Pairs. The score is a standardized T-Score which indicates the number of standard deviations above or below the mean, a T-Score of 50, in 10 point increments. A T-Score of 60 indicates 1 standard deviation above the mean and a T-Score of 40 indicates 1 standard deviation below the mean. A score below 50 indicated cognitive processing below that of an age and gender matched healthy control population. A score above 50 indicates cognitive processing above that of an age and gender matched healthy control population.	at 6 months
Change in Cognition and Working Memory (MATRICS) Verbal Learning	The MATRICS is neurocognitive battery designed to assess cognition. Verbal Learning is a composite score based on the Hopkins Verbal Learning Test-Revised: Immediate Recall. The score is a standardized T-Score which indicates the number of standard deviations above or below the mean, a T-Score of 50, in 10 point increments. A T-Score of 60 indicates 1 standard deviation above the mean and a T-Score of 40 indicates 1 standard deviation below the mean. A score below 50 indicated cognitive processing below that of an age and gender matched healthy control population. A score above 50 indicates cognitive processing above that of an age and gender matched healthy control population.	at 6 months
Change in Cognition and Working Memory (MATRICS) Visual Learning	The MATRICS is neurocognitive battery designed to assess cognition. Visual Learning is a composite score based on the Brief Visuospatial Memory test - Revised: Immediate Recall. The score is a standardized T-Score which indicates the number of standard deviations above or below the mean, a T-Score of 50, in 10 point increments. A T-Score of 60 indicates 1 standard deviation above the mean and a T-Score of 40 indicates 1 standard deviation below the mean. A score below 50 indicated cognitive processing below that of an age and gender matched healthy control population. A score above 50 indicates cognitive processing above that of an age and gender matched healthy control population.	at 6 months
Change in Cognition and Working Memory (MATRICS) Reasoning and Problem Solving	The MATRICS is neurocognitive battery designed to assess cognition. Problem Solving is a composite score based on the NAB Mazes. The score is a standardized T-Score which indicates the number of standard deviations above or below the mean, a T-Score of 50, in 10 point increments. A T-Score of 60 indicates 1 standard deviation above the mean and a T-Score of 40 indicates 1 standard deviation below the mean. A score below 50 indicated cognitive processing below that of an age and gender matched healthy control population. A score above 50 indicates cognitive processing above that of an age and gender matched healthy control population.	at 6 months
Change in Blood Level of Glutathione	Glutathione is a tripeptide comprised of three amino acids (cysteine, glutamic acid, and glycine) and acts as an antioxidant, a free radical scavanger and a detoxifying agent. Glutathione is an important co-factor for the enzyme glutathione peroxidase used in the uptake of amino acids. The level of glutathione is measured in blood cells.	at 6 months
Blood Plasma Level of Cysteine	Cysteine is an amino acid, a building block for proteins and is used throughout the body and was measured in blood plasma.	at 6 months
GPxbc Glutathione Peroxidase Activity in Blood Cells	GPxBC is a measurement of glutathiione peroxidase enzymatic activity in glutathione synthesis and the redox system in blood cells. Measured as umol/min/gHb from blood cells.	at 6 months
Glutamine Brain Level for NAC Group	Glutamine is measured in the medial prefrontal cortex using Magnetic Resonance Spectroscopy (H-MRS) and is a chemical that works to protect the brain from high levels of excitatory chemicals such as glutamate.	at 6 months
Glutamine Brain Level for Placebo Group	Glutamine is measured in the medial prefrontal cortex using Magnetic Resonance Spectroscopy (H-MRS) and is a chemical that works to protect the brain from high levels of excitatory chemicals such as glutamate.	at 6 months
Glutamate Brain Level for NAC Group	Brain marker, glutamate, was measured using Magnetic Resonance Spectroscopy (H-MRS) in the medial prefrontal cortex. Glutamate is an excitatory neurotransmitter in the brain.	at 6 months
Glutamate Brain Level for Placebo Group	Glutamine is measured in the medial prefrontal cortex using Magnetic Resonance Spectroscopy (H-MRS) and is a chemical that works to protect the brain from high levels of excitatory chemicals such as glutamate.	at 6 months
Glutathione Brain Level for NAC Group	measured by H-MRS in the medial prefrontal cortex Brain markers, glutathione was measured using Magnetic Resonance Spectroscopy (H-MRS) in the medial prefrontal cortex. Glutathione is a tripeptide comprised of three amino acids (cysteine, glutamic acid, and glycine) and acts as an antioxidant, a free radical scavanger and a detoxifying agent. Glutathione is an important co-factor for the enzyme glutathione peroxidase used in the uptake of amino acids.	at 6 months
Glutathione Brain Level for Placebo Group	measured by H-MRS in the medial prefrontal cortex Brain markers, glutathione was measured using Magnetic Resonance Spectroscopy (H-MRS) in the medial prefrontal cortex. Glutathione is a tripeptide comprised of three amino acids (cysteine, glutamic acid, and glycine) and acts as an antioxidant, a free radical scavanger and a detoxifying agent. Glutathione is an important co-factor for the enzyme glutathione peroxidase used in the uptake of amino acids.	at 6 months
Myo-Inositol Brain Level for the NAC Group	Myo-Inositol is measured in the medial prefrontal cortex using Magnetic Resonance Spectroscopy (H-MRS)MRS and is a chemical that works to protect the brain from high levels of excitatory chemicals such as glutamate.	at 6 months
Myo-Inositol Brain Level for Placebo Group	Myo-Inositol is measured in the medial prefrontal cortex using Magnetic Resonance Spectroscopy (H-MRS)MRS and is a chemical that works to protect the brain from high levels of excitatory chemicals such as glutamate.	at 6 months

Collaborators and Investigators

• Sponsor: Beth Israel Deaconess Medical Center
• Collaborators: Center de Neurosciences Psychiatrique, Lausanne, Switzerland
• Investigators: Study Director: Ann Cousins, PhD, APRN, Beth Israel Deaconess Medical Center; Study Chair: T. U. Wilson Woo, MD, PhD, Harvard Medical School (HMS and HSDM)

Publications and helpful links

General Publications

• Do KQ, Conus P, Cuenod M. Redox dysregulation and oxidative stress in schizophrenia: nutrigenetics as a challenge in psychiatric disease prevention. World Rev Nutr Diet. 2010;101:131-153. doi: 10.1159/000314518. Epub 2010 Apr 30. No abstract available.

Study record dates

Study Major Dates

• Study Start: May 1, 2011
• Primary Completion (Actual): August 1, 2014
• Study Completion (Actual): August 1, 2014

Study Registration Dates

• First Submitted: May 13, 2011
• First Submitted That Met QC Criteria: May 13, 2011
• First Posted (Estimate): May 16, 2011

Study Record Updates

• Last Update Posted (Actual): July 5, 2017
• Last Update Submitted That Met QC Criteria: June 13, 2017
• Last Verified: June 1, 2017

More Information

Terms related to this study

• Keywords: schizophrenia; schizoaffective; schizophreniform; early schizophrenia spectrum psychosis
• Additional Relevant MeSH Terms: Schizophrenia Spectrum and Other Psychotic Disorders; Schizophrenia; Psychotic Disorders; Mental Disorders; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Protective Agents; Respiratory System Agents; Antioxidants; Antidotes; Free Radical Scavengers; Expectorants; Acetylcysteine; N-monoacetylcystine
• Other Study ID Numbers: 2008P000460; 107865 (Other Identifier: FDA IND)