Clinical trial NCT01339858: The Effect of N-Acetyl Cysteine on Cortical Erosion in Early Stage Schizophrenia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Schizophrenia
Psychotic Disorder NOS
Schizoaffective Disorder
Schizophreniform
Lead sponsor: Indiana University
Sponsor class: OTHER
Collaborators: name: Stanley Medical Research Institute
First posted: 2011-04-21
Enrollment: 60
Sex: ALL
Minimum age (years): 16
Maximum age (years): 35
Standard ages: CHILD
ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Eligibility criteria: 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

Primary outcomes:
measure: Cortical Thickness
timeFrame: 12 months
measure: Cortical Volume
timeFrame: 12 months
Secondary outcomes:
measure: Working Memory
timeFrame: Baseline and 12 months
measure: Number of Participants With Glutamine/Glutamate Level Changes
timeFrame: 12 months
measure: Attention Measures
timeFrame: 12 months
measure: Symptoms of a Psychotic Disorder
timeFrame: 12 months
measure: Cognitive Functioning
timeFrame: Baseline and 12 months
measure: Functional Status
timeFrame: Baseline and 12 months
measure: Mismatch Negativity Voltage Differences
timeFrame: 12 months
measure: Symptoms of a Psychotic Disorder
timeFrame: 12 months
Other outcomes:
Locations:
city: Indianapolis
country: United States
facility: Prevention and Recovery Center for Early Psychosis (PARC)
state: Indiana
city: Indianapolis
country: United States
facility: Indiana University Psychotic Disorders Clinic
state: Indiana
Study officials:
References:
citation: Breier A, Liffick E, Hummer TA, Vohs JL, Yang Z, Mehdiyoun NF, Visco AC, Metzler E, Zhang Y, Francis MM. Effects of 12-month, double-blind N-acetyl cysteine on symptoms, cognition and brain morphology in early phase schizophrenia spectrum disorders. Schizophr Res. 2018 Sep;199:395-402. doi: 10.1016/j.schres.2018.03.012. Epub 2018 Mar 24.