The Effect of N-Acetyl Cysteine on Cortical Erosion in Early Stage Schizophrenia

Schizophrenia is a severe, debilitating illness that typically begins during the teen-age
years and early twenties, and worsens over time as it evolves into a chronic, life-long
disorder. Existing treatments suppress psychotic symptoms but do not prevent the evolution of
underlying disease processes that results in poor, long term outcomes. Recent studies have
shown that progressive erosion of cortical mass occurs during the early stages of
schizophrenia (1-3). The investigators hypothesize that arresting cortical erosion during the
early phases of schizophrenia will prevent subsequent clinical deterioration and the
descending course of illness associated with this disorder. The investigators propose to
establish a research program that will assess the ability of agents with neuroprotective
properties to halt cortical loss and thereby prevent subsequent clinical deterioration.

N-acetyl cysteine (NAC) is an attractive molecule for the proposed study because of two of
its mechanistic properties. First, it is an established neuroprotective agent. NAC is a
precursor to glutathione which is a primary detoxifier of reactive oxygen and other radical
molecules which damage neuronal tissue (4-6). Glutathione deficiencies have been well
documented in schizophrenia (7, 8). Second, NAC modulates glutamate release. NMDA
hypofunction and altered glutamate release have been hypothesized to contribute to the
cortical atrophy observed in early stage schizophrenia (9, 10). NAC has been shown to
antagonize both the phencyclidine (PCP) effects of increased frontal glutamate levels and
induction of social isolation in rodents (11). PCP is a pharmacological model of
schizophrenia. In a controlled clinical trial of patients with chronic schizophrenia, NAC
improved mismatch negativity, a pre-attentive measure of cortical information processing that
has been consistently implicated in the pathophysiology of schizophrenia and has been shown
to correlate with cortical erosion in early stage patients (12, 13). In a double-blind,
placebo controlled clinical trial of chronic schizophrenic patients, NAC significantly
improved general psychopathology scores, negative symptoms and extrapyramidal symptoms (14).
NAC was well tolerated with no significant effects on any safety parameter or adverse events.
The favorable tolerability of NAC has been further demonstrated in a recent study conducted
at IUSM Riley Hospital in children (ages 4 to 12 years) with autism at relatively high doses
(dose range of 900 to 4200 mg/day) in which there were no serious adverse events reported and
NAC was well tolerated (15).

The investigators propose to determine if NAC has disease modifying potential in early stage
schizophrenia. The investigators hypothesize that NAC will improve measures of cortical
integrity in early stage schizophrenia and these brain effects will be related to
improvements in negative symptoms and cognitive functioning. Primary outcome measures in the
trials will be serial assessments of cortical integrity using magnetic resonance structural
(cortical thickness, cortical volume, diffuses tensor imaging, DTI). In addition the
investigators will assess the possible effects of NAC treatment on other parameters linked to
cortical erosion including fMRI coupled with working memory and semantic memory tasks, MR
spectroscopy (cortical glutathione, N-acetylaspartate, and glutamine/glutamate levels) and
electrophysiological measures (e.g., mismatch negativity, P300). The investigators will also
determine the relationship between effects of NAC on negative symptoms, positive symptoms,
functional status, cognition (BACS), and safety parameters; and brain indices.

SUBJECTS DIAGNOSED WITH A PSYCHOTIC DISORDER

Inclusion Criteria:

- Patients with a DSM-IV diagnosis of schizophrenia, schizophreniform, schizoaffective,
psychosis disorder NOS

- Age range 16-35 years

- Male or female

- Within 2 years of the first onset of psychotic symptoms that resulted in
work/school/social dysfunction and/or treatment (PI will review potential subjects who
have been experiencing symptoms >2 years but <5 years and will allow to enter the
trial on a case-by-case basis)

- Ability to provide informed consent and/or assent (all subjects)

- For subjects 16 and 17 years of age, parental/guardian consent

Exclusion Criteria:

- Unstable medical conditions

- Active seizure disorder

- Pregnant or lactating women

- Females unwilling to utilize birth control

- Implanted pacemaker, medication pump, vagal stimulator, deep brain stimulator, TENS
unit, or ventriculoperitoneal shunt (because of MR studies).

- Known IQ less than 70

- DSM-IV-TR diagnosis of substance dependence (with the exception of nicotine or
caffeine dependence)

- Psychotic symptoms secondary to substance use

- Considered a high risk for suicidal acts - active suicidal ideation with intent to act
as determined by clinical interview

HEALTHY CONTROL SUBJECTS

The comparison subjects will consist of 40 healthy normal volunteers recruited from the
community who will be age and gender matched to subjects diagnosed with a psychotic
disorder entering the NAC treatment study

Inclusion Criteria:

1. Age range of 18-30 (inclusive) and able to give voluntary informed consent (Note:
Subjects diagnosed with a psychotic disorder under the age of 18 will be age matched
to control subjects aged 18).

2. Male or Female

Exclusion Criteria:

1. Current severe mental disorder (Schizophrenia, schizophreniform disorder, other
psychotic disorders, bipolar disorder, major depressive disorder)

2. Known/documented IQ < 70

3. Pregnant or lactating women

4. Acute, serious, or unstable medical condition

5. Metallic implants or other contraindication to MRI (including but not limited to:
Implanted pacemaker, medication pump, vagal stimulator, deep brain stimulator, TENS
unit, or ventriculoperitoneal shunt)

6. First degree relative with a psychotic disorder (i.e. schizophrenia, schizophreniform,
schizoaffective, psychosis disorder NOS, substance induced psychosis, major depression
with psychotic features, or bipolar disorder with psychotic features).

7. Current DSM-IV-TR diagnosis of substance abuse or dependence (with the exception of
nicotine or caffeine) as diagnosed within the 6 months prior to screening visit

8. Known history of seizure disorder, head trauma, stroke, traumatic brain injury,
significant loss of consciousness