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

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.

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