Schizophrenia, Related Troubles and Glutathione: Clinical Trial. Effects of Oral Administration of N-Acetylcysteine (NAC) on the Brain Glutathione Level and on the Symptoms of Schizophrenia

Study Overview
=================
Brief Summary
-----------------
The results of the study schizophrenia, related disorders and glutathione conducted at the Laboratory of Psychiatric Neuroscience (LUNEP) DUPA of Lausanne, reinforce the hypothesis proposed that a deficit intracerebral glutathione is a vulnerability factor for Schizophrenia at least for a subgroup of patients. While pursuing the baseline study, it is appropriate now to try to restore a higher level of glutathione in patients to see if this increase is accompanied by an improvement in symptoms, particularly negative symptoms and disorders cognitive, particularly resistant to current therapy. N-acetyl-cystein (NAC) is a precursor of glutathione which is used clinically for various indications, well tolerated even at high doses. The investigators propose a double-blind cross-over with the aim to study if the N-acetyl-cystein (at a dose of oral 2g/day) leads on the one hand a rising glutathione brain (measured in resonance magnetic spectroscopic) and also improved patients' conditions (determined by clinical assessments, psychopathological, neuropsychological, biochemical and physiological), while recording any side effects. As a first step, this study should include at least thirty patients and last for two to three years. It is important to note that this is not a study of medication suggested by a pharmaceutical industry, but a medical search.

Detailed Description
-----------------
The results of the study schizophrenia, related disorders and glutathione conducted at the Laboratory of Psychiatric Neuroscience (LUNEP) DUPA of Lausanne, reinforce the hypothesis proposed that a deficit intracerebral glutathione is a vulnerability factor for Schizophrenia at least for a subgroup of patients. While pursuing the baseline study, it is appropriate now to try to restore a higher level of glutathione in patients to see if this increase is accompanied by an improvement in symptoms, particularly negative symptoms and disorders cognitive, particularly resistant to current therapy. N-acetyl-cysteine (NAC) is a precursor of glutathione which is used clinically for various indications, well tolerated even at high doses. The investigators propose a double-blind cross-over with the aim to study if the N-acetyl-cystein (at a dose of oral 2g/day) leads on the one hand a rising glutathione brain (measured in resonance magnetic spectroscopic) and also improved patients' conditions (determined by clinical assessments, psychopathological, neuropsychological, biochemical and physiological), while recording any side effects. As a first step, this study should include at least thirty patients and last for two to three years. It is important to note that this is not a study of medication suggested by a pharmaceutical industry, but a medical search.

Official Title
-----------------
Schizophrenia, Related Troubles and Glutathione: Clinical Trial. Effects of Oral Administration of N-Acetylcysteine (NAC) on the Brain Glutathione Level and on the Symptoms of Schizophrenia: Double-blind and Crossover Study

Conditions
-----------------
Schizophrenia

Intervention / Treatment
-----------------
* Drug: N-Acetyl-Cysteine (NAC)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: patients (male or female, aged 18 to 65 years, QI>70) meeting the DSM-IV criteria (established by a senior psychiatrist) for schizophrenia and have the capacity to consent to the study. The study population include both inpatients and outpatients who are currently taking at least one of the following:Olanzapine, Clozapine, Haloperidol, Risperidone, Flupenthixol, or Fluphenazine. The following guidelines have been established for potential medication changes that patients may undergo during the course of the trial. dose changes to existing medication (either increases or decreases in dose) will be accepted and participants will be allowed to continue with the trial. A change in primary antipsychotics from one medication to another will require participants to withdrawn from the study. An addiction of another antipsychotic, secondary to the existing antipsychotic treatment (primary antipsychotic) will be acceptable providing that there isn't a complete change from one antipsychotic to another. Exclusion Criteria: pregnancy acute psychotic state, preventing the patient cooperation co-morbidity with drug dependency organic cerebral disease, major somatic diseases abnormal renal, hepatic, thyroid or hematological findings treatment with a regulator of mood(lithium, valproate, topiramate, lamotrigine et carbamazepine) allergy to NAC treatment with antioxidants

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: patients who receive NAC first<br>this group will receive 2g/day of NAC (2 caps of 0.5g twice day)for a duration of 8 weeks first, and after this 8 weeks their receive placebo for 8 weeks. | Drug: N-Acetyl-Cysteine (NAC)<br>* Once included, the patients will be randomly placed in two groups: one group (1) will receive 2 g/day of NAC (2caps of 0.5g twice a day) and the other group (2) a placebo, for a duration of 8 weeks. At the end of the 8 weeks, group (2) will receive NAC and (1) the placebo for another 8 weeks<br>|
| Placebo Comparator: patients who receive placebo first<br>this patients will receive first placebo for a duration of 8 weeks, and after this 8 weeks their receive NAC for 8 weeks | Drug: N-Acetyl-Cysteine (NAC)<br>* Once included, the patients will be randomly placed in two groups: one group (1) will receive 2 g/day of NAC (2caps of 0.5g twice a day) and the other group (2) a placebo, for a duration of 8 weeks. At the end of the 8 weeks, group (2) will receive NAC and (1) the placebo for another 8 weeks<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Positive and Negative Syndrome Scale (PANSS) | Improvment of the negative symptoms, measured with the PANSS: positive and negative syndrome scale. (Score:1= absence of the symptom - 7= extreme symptoms) | 8 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| frankfurt Complaint Questionnaire (FCQ) | Assessment of subjective troubles,  basic symptoms : troubles of perceptive, cognitive or motor functions frequently observed in prodromal or remission phases. | 8 months | 
| Global Assessment of Functioning - (GAF) | Assessment of the psychological, social and professional state of the patient at a given moment. | 8 months | 
| Clinical Global Impression - (CGI) | Allows punctual evaluation of the severity of the disease, of the improvement and of the side effects | 8 months | 
| Neuropsychological evaluation | The neuropsychological tests aim to assess cognitive functions : working memory, attention, planning; also include a WAIS | 8 months | 
| Neurological scales for the assessment of extrapyramidal symptoms | AIMS (Abnormal Involuntary Movements Scale): quantitative assessment of secondary hyperkinesia (excluding tremor) due to neuroleptics. | 8 months | 
| • Magnetic Resonance Spectroscopy (MRS) | A MRS method has originally been developed for the determination of brain GSH levels in vivo (Trabesinger et al., 1999), allowing us to observe a 51% GSH decrease in prefrontal cortex of schizophrenic patients (Do et al., 2000). | 8 months | 
| EEG/evoked potentials | Anomalies of amplitude and latency of the P300 wave evoked under the auditory oddball paradigm are reliable neurophysiological markers of schizophrenia, correlating with the negative symptoms | 8 months | 
| Blood and fibroblasts biochemistry | I. Plasma GSH and metabolites, plasma amino acids, particularly the sulfur containing ones II. activity of enzymes involved in GSH metabolism III. genetic analysis of enzymes involved in GSH metabolism IV. cell counts and tests of hepatic, renal and thyroid functions | 8 months | 
| Neurological scales for the assessment of extrapyramidal symptoms | Simpson-Angus scale for extrapyramidal signs: tremor, rigidity, akinesia. | 8 months | 
| Neurological scales for the assessment of extrapyramidal symptoms | Barnes scale: specific assessment of akathisia. | 8 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Schizophrenia, glutathione, NAC, Neurological scales, Magnetic Resonance Spectroscopy (MRS), EEG/evoked potentials, fibroblasts, patients who receive NAC, patients who receive placebo