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

Phase 1

Completed

• Conditions: Schizophrenia
• Interventions: Drug: N-acetylcysteine (NAC); Drug: Inactive placebo capsule

• Registration Number: NCT01885338
• Lead Sponsor: 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.

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 Timeline

• Study Start: 2013-06
• Study First Submitted: 2013-06-17
• Study First Submitted QC: 2013-06-19
• Study First Posted: 2013-06-24
• Primary Completion: 2014-05
• Study Completion: 2014-05
• Status Verified: 2015-06
• Last Update Submitted: 2015-06-02
• Last Update Posted: 2015-06-04

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 26

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
N-acetylcysteine (NAC)	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.
Inactive placebo capsule	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.

Primary Outcome Measures

Name	Time	Method
EEG: Change in Gamma Synchrony Evoked Power and Phase Synchronization	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.
EEG: Change in Mismatch Negativity Amplitude	Change from baseline to 8 weeks	A passive attention auditory oddball paradigm will be used to assess MMN.
EEG: Change in P300 Amplitude	Change from baseline to 8 weeks	P300 will be measured using an active attention auditory oddball paradigm.

Secondary Outcome Measures

Name	Time	Method
EEG: Change in Visual Cortical Plasticity	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).
Change in MATRICS Consensus Cognitive Battery composite score	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).
Change in Positive and Negative Syndrome Scale (PANSS) total score	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.
Change in Clinical Assessment Interview for Negative Symptoms (CAINS) scores	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).

Trial Locations

Locations (1)

VA West Los Angeles Healthcare Center; 🇺🇸 Los Angeles, California, United States