The Effect of N-Acetyl Cysteine on Cortical Erosion in Early Stage Schizophrenia
Condition: Schizophrenia; Psychotic Disorder NOS; Schizoaffective Disorder; Schizophreniform
MeSH terms: Schizophrenia; Mental Disorders; Psychotic Disorders
Study type: Interventional
Phase: Phase 4

Summary: 
      The primary objective of this study is to determine if NAC, added to existing antipsychotic
      treatment, is superior to placebo for cortical erosion in patients with early stage
      psychosis. The primary hypothesis is that there will be significantly less cortical erosion
      as measured by cortical thickness, cortical volume and cortical white matter density
      (assessed by DTI) in patients treated for 12 months with NAC as compared to those treated
      with placebo. The secondary objectives of this study are to determine if 12 months of NAC
      add-on treatment is superior to placebo for fMRI determined working memory and semantic
      memory tasks, cortical MR spectroscopy measures (glutathione, N-acetylaspartate, and
      glutamine/glutamate levels), electrophysiologically determined attention measures (e.g.,
      mismatch negativity, P300), symptoms, functional measures and cognitive functioning.
    

Detailed description: 
      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.
    

Intervention name(s): N-Acetyl Cysteine; sugar pill
Intervention type(s): Drug; Other
Intervention description(s): NAC and matched placebo will be supplied in unmarked capsules. Each NAC capsule will contain 480 mg of NAC. Dosing will begin at 480 mg/d and titrated up by 480 mg/d each week until a maximum dose of 2880 mg/d (BID) is reached. This approximate dose was effective and well tolerated in a recent study of treatment refractory obsessive-compulsive disorder by Krystal and colleagues at Yale (16). In addition, a double-blind placebo controlled trial recently completed at IUSM Riley Hospital in children (age 4 to 12 years) with autism spectrum disorders used doses ranging from 900 mg/day to 4200 mg/day and reported no serious adverse events and found the agent well tolerated (15). Dose adjustments downward to 1920 mg/d will be permitted if tolerability issues are encountered at the maximum dose; matched placebo will be supplied in unmarked capsules. Dosing regimen will be the same as in the N-Acetyl Cysteine arm.
Intervention MeSH terms: Acetylcysteine; N-monoacetylcystine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Care Provider)
Primary purpose: Treatment