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Trial record 14 of 20 for:    complementary and alternative medicine AND American

N-acetylcysteine (NAC) for Improving Cognitive Dysfunction in Schizophrenia (NACSZ)

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ClinicalTrials.gov Identifier: NCT01885338
Recruitment Status : Completed
First Posted : June 24, 2013
Last Update Posted : June 4, 2015
Sponsor:
Collaborators:
VISN 22 Mental Illness Research, Education, and Clinical Center
American Psychiatric Foundation
Information provided by (Responsible Party):
Michael C. Davis, M.D., Ph.D., VA Greater Los Angeles Healthcare System

Brief Summary:
This study will evaluate the effect of the dietary supplement N-acetylcysteine (NAC) on electrophysiologic (EEG) markers related to cognition, as well as performance on psychological tests measuring cognition. The primary hypothesis is that participants treated with NAC will show improvements in cognitive function, as measured by EEG and performance-based tests.

Condition or disease Intervention/treatment Phase
Schizophrenia Drug: N-acetylcysteine (NAC) Drug: Inactive placebo capsule Phase 1

Detailed Description:

Schizophrenia is a serious mental illness associated with substantial social and occupational dysfunction. While positive psychotic symptoms of schizophrenia often respond to antipsychotic medications, negative symptoms and cognitive impairment are difficult to treat, necessitating novel interventions. Cognitive deficits are an important treatment target because the degree of cognitive impairment is a critical predictor of work, education, and social functioning.

Glutamatergic receptors are among the most promising biological targets for cognitive-enhancing drugs in schizophrenia. Abnormal glutamatergic signaling has long been thought to be important in the pathophysiology of schizophrenia; specifically, reduced NMDA glutamatergic receptor activity on thalamic inhibitory neurons disinhibits glutamatergic neurons projecting to the cortex, which can cause secondary dopaminergic abnormalities and lead to characteristic symptoms, including cognitive deficits. Many electrophysiological (EEG) biomarkers related to cognitive dysfunction in schizophrenia are thought to be linked to deficient NMDA glutamatergic neurotransmission. Additionally, neuroplasticity is thought to involve glutamatergic signaling. This pattern of linkages suggests that correcting impaired NMDA glutamatergic transmission in schizophrenia could lead to enhanced cognitive function and learning.

In this pilot study, we will focus on a promising dietary supplement approach to address glutamatergic deficits, evaluating its effects by EEG biomarkers and performance-based neurocognitive assessments. N-acetylcysteine (NAC) is a modified amino acid that is commonly used as a dietary supplement because of its antioxidant properties. NAC modulates glutamatergic signaling as follows: In the CNS, glial cells take up NAC via cystine-glutamate antiporters, which in turn leads to increased glutamate efflux into the extracellular space. Extracellular glutamate binds to non-synaptic glutamate receptors such as the metabotropic glutamate receptors (mGluR) type 2/3 and type 5. The net result of these events is a normalization of pathologically elevated cortical glutamate levels.

We will assess EEG biomarkers associated with cognitive deficits in schizophrenia, including a recently-described biomarker for visual cortical plasticity. We will also perform a comprehensive assessment of neurocognition with the MATRICS battery, which could suggest whether certain cognitive domains are sensitive to improvement with NAC therapy.

Our primary aim is to determine whether NAC administration will improve NMDA-dependent EEG abnormalities in schizophrenia. We have 3 hypotheses: (1) NAC administration will increase mismatch negativity amplitude as compared to placebo; (2) NAC administration will increase P300 amplitude as compared to placebo; and (3) NAC administration will increase gamma oscillation power and phase synchronization as compared to placebo. We also will examine whether NAC will improve measures of visual neuroplasticity, performance-based measures of neurocognition, and clinical symptoms of schizophrenia.


Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 26 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Dietary Supplement N-acetylcysteine (NAC) as a Novel Complementary Medicine to Improve Cognitive Disfunction in Schizophrenia
Study Start Date : June 2013
Actual Primary Completion Date : May 2014
Actual Study Completion Date : May 2014

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Schizophrenia

Arm Intervention/treatment
Experimental: N-acetylcysteine (NAC)
Capsules containing N-acetylcysteine 600mg, with inactive ingredients of cellulose, L-leucine, and silica used as filler. Dosage is 2 capsules by mouth twice daily for 8 weeks.
Drug: N-acetylcysteine (NAC)
Other Names:
  • N-acetyl-L-cysteine
  • NAC

Placebo Comparator: Inactive placebo capsule
A placebo capsule is used that is identical to the active treatment but lacks NAC. The inactive ingredients in the placebo capsule are cellulose, L-leucine, and silica. Dose is 2 capsules by mouth twice daily for 8 weeks.
Drug: Inactive placebo capsule
Other Names:
  • Placebo capsule
  • Sugar pill




Primary Outcome Measures :
  1. EEG: Change in Mismatch Negativity Amplitude [ Time Frame: Change from baseline to 8 weeks ]
    A passive attention auditory oddball paradigm will be used to assess MMN.

  2. EEG: Change in P300 Amplitude [ Time Frame: Change from baseline to 8 weeks ]
    P300 will be measured using an active attention auditory oddball paradigm.

  3. EEG: Change in Gamma Synchrony Evoked Power and Phase Synchronization [ Time Frame: Change from baseline to 8 weeks ]
    Stimuli will consist of 1-msec 93-dB clicks presented in 500-msec trains presented at 40 Hz, in 3 separate blocks with 200 trials per block. Continuous data will be epoched at -100 to 700 ms relative to stimulus onset and baseline corrected to the average of the prestimulus interval. For evoked gamma power analyses, averages will be computed on a minimum of 120 artifact-free epochs in each block. The averaged epochs across the click trains (0-512 msec) will be transformed into power spectra by fast Fourier transform (FFT). The 40-Hz power spectra will be averaged across 36-45 Hz. Time/frequency intertrial coherence analyses will be performed to assess intertrial coherence of the stimulus-driven EEG signals. In this analysis, coherence ranges from 0 (non-phase-locked random activity) to 1 (activity that is fully locked in phase across individual trials). Responses at electrode Fz will be analyzed.


Secondary Outcome Measures :
  1. EEG: Change in Visual Cortical Plasticity [ Time Frame: Change from baseline to 8 weeks ]
    The paradigm involves assessing visual evoked potentials (VEPs) before and after exposure to tetanizing visual high-frequency stimulation (HFS).

  2. Change in MATRICS Consensus Cognitive Battery composite score [ Time Frame: Change from baseline to 8 weeks ]
    The MCCB was developed as a standardized method to assess cognition in clinical trials of potential cognitive-enhancing drugs. It consists of ten tests which assess seven cognitive domains (processing speed, attention, working memory, verbal learning, visual learning, problem solving and reasoning, and social cognition).

  3. Change in Positive and Negative Syndrome Scale (PANSS) total score [ Time Frame: Change from baseline to 8 weeks ]
    This is a widely-used instrument that assesses 30 different symptoms (categorized into positive, negative, and general psychopathology) on a scale from 1 to 7, based on clinical interview.

  4. Change in Clinical Assessment Interview for Negative Symptoms (CAINS) scores [ Time Frame: Change from baseline to 8 weeks ]
    The CAINS is comprised of two subscales that assess the major negative symptom subdomains: 1) Motivation and Pleasure and 2) Expression. This instrument is administered in a semi-structured clinical interview and each of 13 items is rated on a scale ranging from 0 (no impairment) to 4 (severe deficit).


Other Outcome Measures:
  1. MIRECC Global Assessment of Functioning (MIRECC GAF) [ Time Frame: 4 weeks, 8 weeks ]
    This is a version of the Global Assessment of Functioning scale in which occupational functioning, social functioning, and symptom severity are scored on a scale of 1-100, with lower scores indicating more impairment in each of the three domains.

  2. Clinical Global Impression (CGI-S and CGI-I [ Time Frame: 4 weeks, 8 weeks ]
    The CGI-S (severity scale) is a widely-used rating scale in which the clinician rates the severity of the subject's mental illness, relative to their past experience with patients with the same diagnosis, on a scale from 1-7, with 1 = normal, not at all ill and 7 = extremely ill. The CGI-I (improvement scale) requires the clinician to rate on a scale from 1-7 how much the mental illness has improved or worsened, relative to a baseline state at the beginning of the intervention, where 1 = very much improved and 7 = very much worse.

  3. Udvalg for Kliniske Undersøgelser (UKU) Side Effects Rating Scale: [ Time Frame: 2 weeks, 4 weeks, 8 weeks ]
    This scale was developed as a comprehensive side effect rating scale for psychopharmacologic medications, with 48 side effects organized into categories.

  4. Barnes Akathisia Scale (BAS) [ Time Frame: 4 weeks, 8 weeks ]
    The most widely-used rating scale to assess the presence and severity of akathisia, the BAS comprises 4 items that rate objective and subjective awareness, subjective distress, and global clinical assessment of akathisia.

  5. Columbia-Suicide Severity Rating Scale (C-SSRS) [ Time Frame: 2 weeks, 4 weeks, 8 weeks ]
    This scale was developed as a screening tool to assess ideation and behaviors associated with suicide risk.



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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Meets DSM-IV-TR criteria for schizophrenia.
  2. At least 3 months since any psychiatric hospitalization
  3. At least 1 month since meeting criteria for having a major depressive episode
  4. At least 6 months since any behaviors suggesting any potential danger to self or others
  5. Currently prescribed an antipsychotic medication, with dose not varying >50% over 3 months prior to study participation
  6. No acute medical problems that could interfere with study participation
  7. Chronic medical problems consistently treated and stable for at least 3 months prior to participation
  8. Ability to provide informed consent and cooperate with study procedures

Exclusion Criteria:

  1. Documented history of IQ less than 70 or severe learning disability
  2. History of treatment with electroconvulsive therapy within 6 months prior to study participation
  3. History of neurological or neuropsychiatric condition (e.g., stroke, severe traumatic brain injury, epilepsy, etc.) that could confound assessments
  4. Documented history of persistent substance abuse or dependence within 3 months prior to study participation

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01885338


Locations
United States, California
VA West Los Angeles Healthcare Center
Los Angeles, California, United States, 90073
Sponsors and Collaborators
VA Greater Los Angeles Healthcare System
VISN 22 Mental Illness Research, Education, and Clinical Center
American Psychiatric Foundation
Investigators
Principal Investigator: Stephen R Marder, M.D. VA Greater Los Angeles
Principal Investigator: Michael C Davis, M.D., Ph.D. VA Greater Los Angeles

Publications:

Responsible Party: Michael C. Davis, M.D., Ph.D., Fellow / Physician, VA Greater Los Angeles Healthcare System
ClinicalTrials.gov Identifier: NCT01885338     History of Changes
Other Study ID Numbers: PCC 2013-020208
First Posted: June 24, 2013    Key Record Dates
Last Update Posted: June 4, 2015
Last Verified: June 2015

Keywords provided by Michael C. Davis, M.D., Ph.D., VA Greater Los Angeles Healthcare System:
Schizophrenia
Cognition
Neurocognition
N-Acetylcysteine
NAC
EEG

Additional relevant MeSH terms:
Physiological Effects of Drugs
Schizophrenia
Cognitive Dysfunction
Schizophrenia Spectrum and Other Psychotic Disorders
Mental Disorders
Cognition Disorders
Neurocognitive Disorders
Acetylcysteine
N-monoacetylcystine
Antiviral Agents
Anti-Infective Agents
Expectorants
Respiratory System Agents
Free Radical Scavengers
Antioxidants
Molecular Mechanisms of Pharmacological Action
Protective Agents
Antidotes