N-acetylcysteine (NAC) for Improving Cognitive Dysfunction in Schizophrenia
Condition: Schizophrenia
MeSH terms: Schizophrenia; Cognitive Dysfunction
Study type: Interventional
Phase: Phase 1

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.
    

Intervention name(s): N-acetylcysteine (NAC); Inactive placebo capsule
Intervention type(s): Drug; Drug
Other intervention name(s): N-acetyl-L-cysteine; NAC; Placebo capsule; Sugar pill
Intervention MeSH terms: Acetylcysteine; N-monoacetylcystine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Schizophrenia; Cognition; Neurocognition; N-Acetylcysteine; NAC; EEG