Clinical trial NCT01885338: N-acetylcysteine (NAC) for Improving Cognitive Dysfunction in Schizophrenia
Official title: Dietary Supplement N-acetylcysteine (NAC) as a Novel Complementary Medicine to Improve Cognitive Disfunction in Schizophrenia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Schizophrenia
Keywords: Schizophrenia
Cognition
Neurocognition
N-Acetylcysteine
NAC
EEG
Lead sponsor: VA Greater Los Angeles Healthcare System
Sponsor class: FED
Collaborators: name: VISN 22 Mental Illness Research, Education, and Clinical Center
name: American Psychiatric Foundation
First posted: 2013-06-24
Enrollment: 26
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility 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

Primary outcomes:
measure: EEG: Change in Mismatch Negativity Amplitude
timeFrame: Change from baseline to 8 weeks
measure: EEG: Change in P300 Amplitude
timeFrame: Change from baseline to 8 weeks
measure: EEG: Change in Gamma Synchrony Evoked Power and Phase Synchronization
timeFrame: Change from baseline to 8 weeks
Secondary outcomes:
measure: EEG: Change in Visual Cortical Plasticity
timeFrame: Change from baseline to 8 weeks
measure: Change in MATRICS Consensus Cognitive Battery composite score
timeFrame: Change from baseline to 8 weeks
measure: Change in Positive and Negative Syndrome Scale (PANSS) total score
timeFrame: Change from baseline to 8 weeks
measure: Change in Clinical Assessment Interview for Negative Symptoms (CAINS) scores
timeFrame: Change from baseline to 8 weeks
Other outcomes:
measure: MIRECC Global Assessment of Functioning (MIRECC GAF)
timeFrame: 4 weeks, 8 weeks
measure: Clinical Global Impression (CGI-S and CGI-I
timeFrame: 4 weeks, 8 weeks
measure: Udvalg for Kliniske Undersøgelser (UKU) Side Effects Rating Scale:
timeFrame: 2 weeks, 4 weeks, 8 weeks
measure: Barnes Akathisia Scale (BAS)
timeFrame: 4 weeks, 8 weeks
measure: Columbia-Suicide Severity Rating Scale (C-SSRS)
timeFrame: 2 weeks, 4 weeks, 8 weeks
Locations:
city: Los Angeles
country: United States
facility: VA West Los Angeles Healthcare Center
state: California
Study officials:
affiliation: VA Greater Los Angeles
name: Stephen R Marder, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: VA Greater Los Angeles
name: Michael C Davis, M.D., Ph.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.