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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

Primary Purpose

Schizophrenia

Status

Completed

Phase

Phase 1

Locations

Study Type

Interventional

Intervention

N-Acetyl-Cysteine (NAC)

About this trial

This is an interventional treatment trial for Schizophrenia focused on measuring Schizophrenia, glutathione, NAC, Neurological scales, Magnetic Resonance Spectroscopy (MRS), EEG/evoked potentials, fibroblasts, patients who receive NAC, patients who receive placebo

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

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A change in primary antipsychotics from one medication to another will require participants to withdrawn from the study.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

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

patients who receive NAC first

patients who receive placebo first

Arm Description

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.

this patients will receive first placebo for a duration of 8 weeks, and after this 8 weeks their receive NAC for 8 weeks

Outcomes

Primary Outcome Measures

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)

Secondary Outcome Measures

frankfurt Complaint Questionnaire (FCQ)

Assessment of subjective troubles, " basic symptoms ": troubles of perceptive, cognitive or motor functions frequently observed in prodromal or remission phases.

Global Assessment of Functioning - (GAF)

Assessment of the psychological, social and professional state of the patient at a given moment.

Clinical Global Impression - (CGI)

Allows punctual evaluation of the severity of the disease, of the improvement and of the side effects

Neuropsychological evaluation

The neuropsychological tests aim to assess cognitive functions : working memory, attention, planning; also include a WAIS

Neurological scales for the assessment of extrapyramidal symptoms

AIMS (Abnormal Involuntary Movements Scale): quantitative assessment of secondary hyperkinesia (excluding tremor) due to neuroleptics.

• 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).

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

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

Neurological scales for the assessment of extrapyramidal symptoms

Simpson-Angus scale for extrapyramidal signs: tremor, rigidity, akinesia.

Neurological scales for the assessment of extrapyramidal symptoms

Barnes scale: specific assessment of akathisia.

Full Information

NCT ID

NCT01506765

First Posted

January 3, 2012

Last Updated

January 17, 2012

Sponsor

Centre Hospitalier Universitaire Vaudois

1. Study Identification

Unique Protocol Identification Number

NCT01506765

Brief 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

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

Study Type

Interventional

2. Study Status

Record Verification Date

January 2012

Overall Recruitment Status

Completed

Study Start Date

August 2003 (undefined)

Primary Completion Date

December 2004 (Actual)

Study Completion Date

September 2006 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Centre Hospitalier Universitaire Vaudois

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Schizophrenia

Keywords

Schizophrenia, glutathione, NAC, Neurological scales, Magnetic Resonance Spectroscopy (MRS), EEG/evoked potentials, fibroblasts, patients who receive NAC, patients who receive placebo

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Crossover Assignment

Masking

ParticipantCare ProviderInvestigator

Allocation

Randomized

Enrollment

13 (Actual)

8. Arms, Groups, and Interventions

Arm Title

patients who receive NAC first

Arm Type

Active Comparator

Arm Description

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.

Arm Title

patients who receive placebo first

Arm Type

Placebo Comparator

Arm Description

this patients will receive first placebo for a duration of 8 weeks, and after this 8 weeks their receive NAC for 8 weeks

Intervention Type

Drug

Intervention Name(s)

N-Acetyl-Cysteine (NAC)

Intervention Description

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

Primary Outcome Measure Information:

Title

Positive and Negative Syndrome Scale (PANSS)

Description

Improvment of the negative symptoms, measured with the PANSS: positive and negative syndrome scale". (Score:1= absence of the symptom - 7= extreme symptoms)

Time Frame

8 months

Secondary Outcome Measure Information:

Title

frankfurt Complaint Questionnaire (FCQ)

Description

Assessment of subjective troubles, " basic symptoms ": troubles of perceptive, cognitive or motor functions frequently observed in prodromal or remission phases.

Time Frame

8 months

Title

Global Assessment of Functioning - (GAF)

Description

Assessment of the psychological, social and professional state of the patient at a given moment.

Time Frame

8 months

Title

Clinical Global Impression - (CGI)

Description

Allows punctual evaluation of the severity of the disease, of the improvement and of the side effects

Time Frame

8 months

Title

Neuropsychological evaluation

Description

The neuropsychological tests aim to assess cognitive functions : working memory, attention, planning; also include a WAIS

Time Frame

8 months

Title

Neurological scales for the assessment of extrapyramidal symptoms

Description

AIMS (Abnormal Involuntary Movements Scale): quantitative assessment of secondary hyperkinesia (excluding tremor) due to neuroleptics.

Time Frame

8 months

Title

• Magnetic Resonance Spectroscopy (MRS)

Description

Time Frame

8 months

Title

EEG/evoked potentials

Description

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

Time Frame

8 months

Title

Blood and fibroblasts biochemistry

Description

Time Frame

8 months

Title

Neurological scales for the assessment of extrapyramidal symptoms

Description

Simpson-Angus scale for extrapyramidal signs: tremor, rigidity, akinesia.

Time Frame

8 months

Title

Neurological scales for the assessment of extrapyramidal symptoms

Description

Barnes scale: specific assessment of akathisia.

Time Frame

8 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

65 Years

Accepts Healthy Volunteers

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Kim Do, Professor

Organizational Affiliation

CNP/ LUNEP

Official's Role

Study Director

12. IPD Sharing Statement

Citations:

PubMed Identifier

11029642

Citation

Do KQ, Trabesinger AH, Kirsten-Kruger M, Lauer CJ, Dydak U, Hell D, Holsboer F, Boesiger P, Cuenod M. Schizophrenia: glutathione deficit in cerebrospinal fluid and prefrontal cortex in vivo. Eur J Neurosci. 2000 Oct;12(10):3721-8. doi: 10.1046/j.1460-9568.2000.00229.x.

Results Reference

background

PubMed Identifier

10704955

Citation

Mathalon DH, Ford JM, Pfefferbaum A. Trait and state aspects of P300 amplitude reduction in schizophrenia: a retrospective longitudinal study. Biol Psychiatry. 2000 Mar 1;47(5):434-49. doi: 10.1016/s0006-3223(99)00277-2.

Results Reference

background

PubMed Identifier

12815674

Citation

Terpstra M, Henry PG, Gruetter R. Measurement of reduced glutathione (GSH) in human brain using LCModel analysis of difference-edited spectra. Magn Reson Med. 2003 Jul;50(1):19-23. doi: 10.1002/mrm.10499.

Results Reference

background

PubMed Identifier

10440953

Citation

Trabesinger AH, Weber OM, Duc CO, Boesiger P. Detection of glutathione in the human brain in vivo by means of double quantum coherence filtering. Magn Reson Med. 1999 Aug;42(2):283-9. doi: 10.1002/(sici)1522-2594(199908)42:23.0.co;2-q.

Results Reference

background

PubMed Identifier

22383949

Citation

Carmeli C, Knyazeva MG, Cuenod M, Do KQ. Glutathione precursor N-acetyl-cysteine modulates EEG synchronization in schizophrenia patients: a double-blind, randomized, placebo-controlled trial. PLoS One. 2012;7(2):e29341. doi: 10.1371/journal.pone.0029341. Epub 2012 Feb 22.

Results Reference

derived

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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

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