- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01885338
N-acetylcysteine (NAC) for Improving Cognitive Dysfunction in Schizophrenia (NACSZ)
Dietary Supplement N-acetylcysteine (NAC) as a Novel Complementary Medicine to Improve Cognitive Disfunction in Schizophrenia
Study Overview
Status
Conditions
Intervention / Treatment
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
Enrollment (Actual)
Phase
- Phase 1
Contacts and Locations
Study Locations
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California
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Los Angeles, California, United States, 90073
- VA West Los Angeles Healthcare Center
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Meets DSM-IV-TR criteria for schizophrenia.
- At least 3 months since any psychiatric hospitalization
- At least 1 month since meeting criteria for having a major depressive episode
- At least 6 months since any behaviors suggesting any potential danger to self or others
- Currently prescribed an antipsychotic medication, with dose not varying >50% over 3 months prior to study participation
- No acute medical problems that could interfere with study participation
- Chronic medical problems consistently treated and stable for at least 3 months prior to participation
- Ability to provide informed consent and cooperate with study procedures
Exclusion Criteria:
- Documented history of IQ less than 70 or severe learning disability
- History of treatment with electroconvulsive therapy within 6 months prior to study participation
- History of neurological or neuropsychiatric condition (e.g., stroke, severe traumatic brain injury, epilepsy, etc.) that could confound assessments
- Documented history of persistent substance abuse or dependence within 3 months prior to study participation
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Quadruple
Arms and Interventions
Participant Group / 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.
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Other Names:
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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.
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Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
EEG: Change in Mismatch Negativity Amplitude
Time Frame: Change from baseline to 8 weeks
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A passive attention auditory oddball paradigm will be used to assess MMN.
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Change from baseline to 8 weeks
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EEG: Change in P300 Amplitude
Time Frame: Change from baseline to 8 weeks
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P300 will be measured using an active attention auditory oddball paradigm.
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Change from baseline to 8 weeks
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EEG: Change in Gamma Synchrony Evoked Power and Phase Synchronization
Time Frame: Change from baseline to 8 weeks
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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.
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Change from baseline to 8 weeks
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
EEG: Change in Visual Cortical Plasticity
Time Frame: Change from baseline to 8 weeks
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The paradigm involves assessing visual evoked potentials (VEPs) before and after exposure to tetanizing visual high-frequency stimulation (HFS).
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Change from baseline to 8 weeks
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Change in MATRICS Consensus Cognitive Battery composite score
Time Frame: Change from baseline to 8 weeks
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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).
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Change from baseline to 8 weeks
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Change in Positive and Negative Syndrome Scale (PANSS) total score
Time Frame: Change from baseline to 8 weeks
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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.
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Change from baseline to 8 weeks
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Change in Clinical Assessment Interview for Negative Symptoms (CAINS) scores
Time Frame: Change from baseline to 8 weeks
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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).
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Change from baseline to 8 weeks
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Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
MIRECC Global Assessment of Functioning (MIRECC GAF)
Time Frame: 4 weeks, 8 weeks
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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.
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4 weeks, 8 weeks
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Clinical Global Impression (CGI-S and CGI-I
Time Frame: 4 weeks, 8 weeks
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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.
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4 weeks, 8 weeks
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Udvalg for Kliniske Undersøgelser (UKU) Side Effects Rating Scale:
Time Frame: 2 weeks, 4 weeks, 8 weeks
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This scale was developed as a comprehensive side effect rating scale for psychopharmacologic medications, with 48 side effects organized into categories.
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2 weeks, 4 weeks, 8 weeks
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Barnes Akathisia Scale (BAS)
Time Frame: 4 weeks, 8 weeks
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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.
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4 weeks, 8 weeks
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Columbia-Suicide Severity Rating Scale (C-SSRS)
Time Frame: 2 weeks, 4 weeks, 8 weeks
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This scale was developed as a screening tool to assess ideation and behaviors associated with suicide risk.
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2 weeks, 4 weeks, 8 weeks
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Collaborators and Investigators
Collaborators
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 and helpful links
General Publications
- Berk M, Malhi GS, Gray LJ, Dean OM. The promise of N-acetylcysteine in neuropsychiatry. Trends Pharmacol Sci. 2013 Mar;34(3):167-77. doi: 10.1016/j.tips.2013.01.001. Epub 2013 Jan 29.
- Cabungcal JH, Steullet P, Kraftsik R, Cuenod M, Do KQ. Early-life insults impair parvalbumin interneurons via oxidative stress: reversal by N-acetylcysteine. Biol Psychiatry. 2013 Mar 15;73(6):574-82. doi: 10.1016/j.biopsych.2012.09.020. Epub 2012 Nov 7.
- Shungu DC. N-acetylcysteine for the treatment of glutathione deficiency and oxidative stress in schizophrenia. Biol Psychiatry. 2012 Jun 1;71(11):937-8. doi: 10.1016/j.biopsych.2012.03.025. No abstract available.
- Carmeli C, Knyazeva MG, Cuenod M, Do KQ. Glutathione precursor N-acetyl-cysteine modulates EEG synchronization in schizophrenia patients: a double-blind, randomized, placebo-controlled trial. PLoS One. 2012;7(2):e29341. doi: 10.1371/journal.pone.0029341. Epub 2012 Feb 22.
- das Neves Duarte JM, Kulak A, Gholam-Razaee MM, Cuenod M, Gruetter R, Do KQ. N-acetylcysteine normalizes neurochemical changes in the glutathione-deficient schizophrenia mouse model during development. Biol Psychiatry. 2012 Jun 1;71(11):1006-14. doi: 10.1016/j.biopsych.2011.07.035. Epub 2011 Sep 25.
- Dean O, Giorlando F, Berk M. N-acetylcysteine in psychiatry: current therapeutic evidence and potential mechanisms of action. J Psychiatry Neurosci. 2011 Mar;36(2):78-86. doi: 10.1503/jpn.100057.
- Berk M, Copolov D, Dean O, Lu K, Jeavons S, Schapkaitz I, Anderson-Hunt M, Judd F, Katz F, Katz P, Ording-Jespersen S, Little J, Conus P, Cuenod M, Do KQ, Bush AI. N-acetyl cysteine as a glutathione precursor for schizophrenia--a double-blind, randomized, placebo-controlled trial. Biol Psychiatry. 2008 Sep 1;64(5):361-8. doi: 10.1016/j.biopsych.2008.03.004. Epub 2008 Apr 23.
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Mental Disorders
- Neurocognitive Disorders
- Schizophrenia Spectrum and Other Psychotic Disorders
- Cognition Disorders
- Schizophrenia
- Cognitive Dysfunction
- 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
- PCC 2013-020208
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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