Glutathione precursor, N-acetyl-cysteine, improves mismatch negativity in schizophrenia patients.

In schizophrenia patients, glutathione dysregulation at the gene, protein and functional levels, leads to N-methyl-D-aspartate (NMDA) receptor hypofunction. These patients also exhibit deficits in auditory sensory processing that manifests as impaired mismatch negativity (MMN), which is an auditory evoked potential (AEP) component related to NMDA receptor function. N-acetyl-cysteine (NAC), a glutathione precursor, was administered to patients to determine whether increased levels of brain glutathione would improve MMN and by extension NMDA function. A randomized, double-blind, cross-over protocol was conducted, entailing the administration of NAC (2 g/day) for 60 days and then placebo for another 60 days (or vice versa). 128-channel AEPs were recorded during a frequency oddball discrimination task at protocol onset, at the point of cross-over, and at the end of the study. At the onset of the protocol, the MMN of patients was significantly impaired compared to sex- and age- matched healthy controls (p=0.003), without any evidence of concomitant P300 component deficits. Treatment with NAC significantly improved MMN generation compared with placebo (p=0.025) without any measurable effects on the P300 component. MMN improvement was observed in the absence of robust changes in assessments of clinical severity, though the latter was observed in a larger and more prolonged clinical study. This pattern suggests that MMN enhancement may precede changes to indices of clinical severity, highlighting the possible utility AEPs as a biomarker of treatment efficacy. The improvement of this functional marker may indicate an important pathway towards new therapeutic strategies that target glutathione dysregulation in schizophrenia.

Specific vs general cognitive remediation for executive functioning in schizophrenia: a multicenter randomized trial.

BACKGROUND: This study assesses the benefits of an individualized therapy (RECOS program) compared with the more general cognitive remediation therapy (CRT). METHODS: 138 participants took part with 65 randomized to CRT and 73 to RECOS. In the RECOS group, participants were directed towards one of five training modules (verbal memory, visuo-spatial memory and attention, working memory, selective attention or reasoning) corresponding to their key cognitive concern whereas the CRT group received a standard program. The main outcome was the total score on BADS (Behavioural Assessment of Dysexecutive Syndrome) and the secondary outcomes were: cognition (executive functions; selective attention; visuospatial memory and attention; verbal memory; working memory) and clinical measures (symptoms; insight; neurocognitive complaints; self-esteem). All outcomes were assessed at baseline (T1), week 12 (posttherapy, T2), and follow-up (week 36, i.e., 6months posttherapy, T3). RESULTS: No difference was shown for the main outcome. A significant improvement was found for BADS' profile score for RECOS at T2 and T3, and for CRT at T3. Change in BADS in the RECOS and CRT arms were not significantly different between T1 and T2 (+0.86, p=0.108), or between T1 and T3 (+0.36, p=0.540). Significant improvements were found in several secondary outcomes including cognition (executive functions, selective attention, verbal memory, and visuospatial abilities) and clinician measures (symptoms and awareness to be hampered by cognitive deficits in everyday) in both treatment arms following treatment. Self-esteem improved only in RECOS arm at T3, and working memory improved only in CRT arm at T2 and T3, but there were no differences in changes between arms. CONCLUSIONS: RECOS (specific remediation) and CRT (general remediation) globally showed similar efficacy in the present trial.

Dysconnection topography in schizophrenia revealed with state-space analysis of EEG.

BACKGROUND: The dysconnection hypothesis has been proposed to account for pathophysiological mechanisms underlying schizophrenia. Widespread structural changes suggesting abnormal connectivity in schizophrenia have been imaged. A functional counterpart of the structural maps would be the EEG synchronization maps. However, due to the limits of currently used bivariate methods, functional correlates of dysconnection are limited to the isolated measurements of synchronization between preselected pairs of EEG signals. METHODS/RESULTS: To reveal a whole-head synchronization topography in schizophrenia, we applied a new method of multivariate synchronization analysis called S-estimator to the resting dense-array (128 channels) EEG obtained from 14 patients and 14 controls. This method determines synchronization from the embedding dimension in a state-space domain based on the theoretical consequence of the cooperative behavior of simultaneous time series-the shrinking of the state-space embedding dimension. The S-estimator imaging revealed a specific synchronization landscape in schizophrenia patients. Its main features included bilaterally increased synchronization over temporal brain regions and decreased synchronization over the postcentral/parietal region neighboring the midline. The synchronization topography was stable over the course of several months and correlated with the severity of schizophrenia symptoms. In particular, direct correlations linked positive, negative, and general psychopathological symptoms to the hyper-synchronized temporal clusters over both hemispheres. Along with these correlations, general psychopathological symptoms inversely correlated within the hypo-synchronized postcentral midline region. While being similar to the structural maps of cortical changes in schizophrenia, the S-maps go beyond the topography limits, demonstrating a novel aspect of the abnormalities of functional cooperation: namely, regionally reduced or enhanced connectivity. CONCLUSION/SIGNIFICANCE: The new method of multivariate synchronization significantly boosts the potential of EEG as an imaging technique compatible with other imaging modalities. Its application to schizophrenia research shows that schizophrenia can be explained within the concept of neural dysconnection across and within large-scale brain networks.

Self-reported adherence versus pill count in Parkinson's disease: the NET-PD experience.

PURPOSE: To compare the Morisky medication adherence questionnaire to pill counts as measures of adherence in the NET-PD futility clinical trials. BACKGROUND: Like in other chronic diseases, non-adherence with medications occurs in Parkinson's disease (PD), although nonadherence has not been of significant concern in most PD clinical trials. The most common approach to assessment is to do a pill count at each visit. The simple, 4-question Morisky medication adherence questionnaire may provide an alternative approach to monitoring treatment adherence in PD. METHODS: Adherence data from two NET-PD Phase II clinical trials enrolling a total of 413 participants were analyzed. The association between demographic and clinical characteristics and adherence was explored. RESULTS: Ninety-percent of participants took 80% or more of the study drug. However, the Morisky medication adherence questionnaires showed 56% report high and 44% report medium adherence. Agreement between the two measures is fair (ICC = 0.40). CONCLUSIONS: Overall adherence as assessed by pill count appears high. The Morisky medication adherence questionnaire may be useful in PD clinical trials, since it is moderately correlated to pill count and may be more sensitive to nonadherence.

Impaired glutathione synthesis in schizophrenia: convergent genetic and functional evidence.

Schizophrenia is a complex multifactorial brain disorder with a genetic component. Convergent evidence has implicated oxidative stress and glutathione (GSH) deficits in the pathogenesis of this disease. The aim of the present study was to test whether schizophrenia is associated with a deficit of GSH synthesis. Cultured skin fibroblasts from schizophrenia patients and control subjects were challenged with oxidative stress, and parameters of the rate-limiting enzyme for the GSH synthesis, the glutamate cysteine ligase (GCL), were measured. Stressed cells of patients had a 26% (P = 0.002) decreased GCL activity as compared with controls. This reduction correlated with a 29% (P < 0.001) decreased protein expression of the catalytic GCL subunit (GCLC). Genetic analysis of a trinucleotide repeat (TNR) polymorphism in the GCLC gene showed a significant association with schizophrenia in two independent case-control studies. The most common TNR genotype 7/7 was more frequent in controls [odds ratio (OR) = 0.6, P = 0.003], whereas the rarest TNR genotype 8/8 was three times more frequent in patients (OR = 3.0, P = 0.007). Moreover, subjects with disease-associated genotypes had lower GCLC protein expression (P = 0.017), GCL activity (P = 0.037), and GSH contents (P = 0.004) than subjects with genotypes that were more frequent in controls. Taken together, the study provides genetic and functional evidence that an impaired capacity to synthesize GSH under conditions of oxidative stress is a vulnerability factor for schizophrenia.

Schizophrenia and oxidative stress: glutamate cysteine ligase modifier as a susceptibility gene.

Oxidative stress could be involved in the pathophysiology of schizophrenia, a major psychiatric disorder. Glutathione (GSH), a redox regulator, is decreased in patients' cerebrospinal fluid and prefrontal cortex. The gene of the key GSH-synthesizing enzyme, glutamate cysteine ligase modifier (GCLM) subunit, is strongly associated with schizophrenia in two case-control studies and in one family study. GCLM gene expression is decreased in patients' fibroblasts. Thus, GSH metabolism dysfunction is proposed as one of the vulnerability factors for schizophrenia.