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Glutathione precursor N-acetyl-cysteine modulates EEG synchronization in schizophrenia patients: a double-blind, randomized, placebo-controlled trial.

Carmeli C, Knyazeva MG, Cuénod M, Do KQ - PLoS ONE (2012)

Bottom Line: In this proof of concept study, the treatment with NAC significantly increased MPS compared to placebo over the left parieto-temporal, the right temporal, and the bilateral prefrontal regions.These changes were robust both at the group and at the individual level.Therefore, significant changes in EEG synchronization induced by NAC administration may precede clinically detectable improvement, highlighting its possible utility as a biomarker of treatment efficacy.

View Article: PubMed Central - PubMed

Affiliation: Center for Psychiatric Neuroscience, Department of Psychiatry, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland.

ABSTRACT

Unlabelled: Glutathione (GSH) dysregulation at the gene, protein, and functional levels has been observed in schizophrenia patients. Together with disease-like anomalies in GSH deficit experimental models, it suggests that such redox dysregulation can play a critical role in altering neural connectivity and synchronization, and thus possibly causing schizophrenia symptoms. To determine whether increased GSH levels would modulate EEG synchronization, N-acetyl-cysteine (NAC), a glutathione precursor, was administered to patients in a randomized, double-blind, crossover protocol for 60 days, followed by placebo for another 60 days (or vice versa). We analyzed whole-head topography of the multivariate phase synchronization (MPS) for 128-channel resting-state EEGs that were recorded at the onset, at the point of crossover, and at the end of the protocol. In this proof of concept study, the treatment with NAC significantly increased MPS compared to placebo over the left parieto-temporal, the right temporal, and the bilateral prefrontal regions. These changes were robust both at the group and at the individual level. Although MPS increase was observed in the absence of clinical improvement at a group level, it correlated with individual change estimated by Liddle's disorganization scale. Therefore, significant changes in EEG synchronization induced by NAC administration may precede clinically detectable improvement, highlighting its possible utility as a biomarker of treatment efficacy.

Trial registration: ClinicalTrials.gov NCT01506765.

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Related in: MedlinePlus

Enrollment, randomization, withdrawals, and completion of the 2 treatment phases (n = 11).
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pone-0029341-g001: Enrollment, randomization, withdrawals, and completion of the 2 treatment phases (n = 11).

Mentions: The CONSORT [31] flowchart of the trial is reported in Fig. 1. Eleven patients (nine men; two women; aged 31.9±3.4 years; mean±standard error) meeting DSM-IV criteria for schizophrenia were recruited from the ambulatory Schizophrenia Service of the Department of Psychiatry of the Centre Hospitalier Universitaire Vaudois by an experienced psychiatrist and a psychologist well trained in Diagnostic Interview for Genetic Studies. The mean duration of illness was 9.4±2.5 years. All patients received atypical antipsychotics except one who was drug-naïve. The complete demographic and clinical characteristics of participants were described in [32]. Among the 11 patients, 9 participated in the clinical trial and 8 completed the entire study, including EEG recordings at crossover and at the end of the study. The two patients who withdrew from the study reported that it was too demanding for them. Of the eight patients who completed the entire study, six were in the group that first received NAC and then placebo; the remaining two received placebo first and then NAC. As reported in [29], no side-effects due to NAC have been observed. Both patients and investigators were blinded until the time of analysis, when data pooling necessitated unblinding. Recruited patients gave fully informed written consent, and the Ethics Committee of the Faculty of Biology and Medicine of the University of Lausanne approved all procedures. All 11 patients underwent the Diagnostic Interview for Genetic Studies, developed by the NIMH [33], [34], and remained on their usual antipsychotic medication for the duration of the trial both in terms of type and dose of medication. Recently the effects of NAC on auditory sensory processing as manifested by mismatch negativity, a component of auditory evoked potential related to NMDA receptor function, were studied in this group of patients [32].


Glutathione precursor N-acetyl-cysteine modulates EEG synchronization in schizophrenia patients: a double-blind, randomized, placebo-controlled trial.

Carmeli C, Knyazeva MG, Cuénod M, Do KQ - PLoS ONE (2012)

Enrollment, randomization, withdrawals, and completion of the 2 treatment phases (n = 11).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3285150&req=5

pone-0029341-g001: Enrollment, randomization, withdrawals, and completion of the 2 treatment phases (n = 11).
Mentions: The CONSORT [31] flowchart of the trial is reported in Fig. 1. Eleven patients (nine men; two women; aged 31.9±3.4 years; mean±standard error) meeting DSM-IV criteria for schizophrenia were recruited from the ambulatory Schizophrenia Service of the Department of Psychiatry of the Centre Hospitalier Universitaire Vaudois by an experienced psychiatrist and a psychologist well trained in Diagnostic Interview for Genetic Studies. The mean duration of illness was 9.4±2.5 years. All patients received atypical antipsychotics except one who was drug-naïve. The complete demographic and clinical characteristics of participants were described in [32]. Among the 11 patients, 9 participated in the clinical trial and 8 completed the entire study, including EEG recordings at crossover and at the end of the study. The two patients who withdrew from the study reported that it was too demanding for them. Of the eight patients who completed the entire study, six were in the group that first received NAC and then placebo; the remaining two received placebo first and then NAC. As reported in [29], no side-effects due to NAC have been observed. Both patients and investigators were blinded until the time of analysis, when data pooling necessitated unblinding. Recruited patients gave fully informed written consent, and the Ethics Committee of the Faculty of Biology and Medicine of the University of Lausanne approved all procedures. All 11 patients underwent the Diagnostic Interview for Genetic Studies, developed by the NIMH [33], [34], and remained on their usual antipsychotic medication for the duration of the trial both in terms of type and dose of medication. Recently the effects of NAC on auditory sensory processing as manifested by mismatch negativity, a component of auditory evoked potential related to NMDA receptor function, were studied in this group of patients [32].

Bottom Line: In this proof of concept study, the treatment with NAC significantly increased MPS compared to placebo over the left parieto-temporal, the right temporal, and the bilateral prefrontal regions.These changes were robust both at the group and at the individual level.Therefore, significant changes in EEG synchronization induced by NAC administration may precede clinically detectable improvement, highlighting its possible utility as a biomarker of treatment efficacy.

View Article: PubMed Central - PubMed

Affiliation: Center for Psychiatric Neuroscience, Department of Psychiatry, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland.

ABSTRACT

Unlabelled: Glutathione (GSH) dysregulation at the gene, protein, and functional levels has been observed in schizophrenia patients. Together with disease-like anomalies in GSH deficit experimental models, it suggests that such redox dysregulation can play a critical role in altering neural connectivity and synchronization, and thus possibly causing schizophrenia symptoms. To determine whether increased GSH levels would modulate EEG synchronization, N-acetyl-cysteine (NAC), a glutathione precursor, was administered to patients in a randomized, double-blind, crossover protocol for 60 days, followed by placebo for another 60 days (or vice versa). We analyzed whole-head topography of the multivariate phase synchronization (MPS) for 128-channel resting-state EEGs that were recorded at the onset, at the point of crossover, and at the end of the protocol. In this proof of concept study, the treatment with NAC significantly increased MPS compared to placebo over the left parieto-temporal, the right temporal, and the bilateral prefrontal regions. These changes were robust both at the group and at the individual level. Although MPS increase was observed in the absence of clinical improvement at a group level, it correlated with individual change estimated by Liddle's disorganization scale. Therefore, significant changes in EEG synchronization induced by NAC administration may precede clinically detectable improvement, highlighting its possible utility as a biomarker of treatment efficacy.

Trial registration: ClinicalTrials.gov NCT01506765.

Show MeSH
Related in: MedlinePlus