Coordinate Regulation of Glutathione Biosynthesis and Release by Nrf2-expressing Glia Potently Protects Neurons from Oxidative Stress

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. Apr, 2003  |  Pubmed ID: 12716947

Astrocytes have a higher antioxidant potential in comparison to neurons. Pathways associated with this selective advantage include the transcriptional regulation of antioxidant enzymes via the action of the Cap'n'Collar transcription factor Nrf2 at the antioxidant response element (ARE). Here we show that Nrf2 overexpression can reengineer neurons to express this glial pathway and enhance antioxidant gene expression. However, Nrf2-mediated protection from oxidative stress is conferred primarily by glia in mixed cultures. The antioxidant properties of Nrf2-overexpressing glia are more pronounced than those of neurons, and a relatively small number of these glia (< 1% of total cell number added) could protect fully cocultured naive neurons from oxidative glutamate toxicity associated with glutathione (GSH) depletion. Microarray and biochemical analyses indicate a coordinated upregulation of enzymes involved in GSH biosynthesis (xCT cystine antiporter, gamma-glutamylcysteine synthetase, and GSH synthase), use (glutathione S-transferase and glutathione reductase), and export (multidrug resistance protein 1) with Nrf2 overexpression, leading to an increase in both media and intracellular GSH. Selective inhibition of glial GSH synthesis and the supplementation of media GSH indicated that an Nrf2-dependent increase in glial GSH synthesis was both necessary and sufficient for the protection of neurons, respectively. Neuroprotection was not limited to overexpression of Nrf2, because activation of endogenous glial Nrf2 by the small molecule ARE inducer, tert-butylhydroquinone, also protected against oxidative glutamate toxicity.

Real-world Implementation of Early Intervention in Psychosis: Resources, Funding Models and Evidence-based Practice

World Psychiatry : Official Journal of the World Psychiatric Association (WPA). Oct, 2008  |  Pubmed ID: 18836540

Potential Endophenotype for Schizophrenia: Neurological Soft Signs

Annals of the Academy of Medicine, Singapore. May, 2009  |  Pubmed ID: 19521640

Neurological soft signs (NSS) are suggested as a candidate endophenotype for schizophrenia. This article aims to review relevant literature and discuss the role of NSS in understanding schizophrenia.

Phenotyping Psychosis: Room for Neurocomputational and Content-dependent Cognitive Endophenotypes?

Cognitive Neuropsychiatry. 2009  |  Pubmed ID: 19634039

The endophenotype research strategy aims at reducing complex clinical phenomena to reveal a more tractable mapping to underlying genes. Cognitive dysfunctions have been widely pursued as target endophenotype in schizophrenia. We critically discuss the promise and limitations of this approach.

Early Intervention for Psychosis in Hong Kong--the EASY Programme

Early Intervention in Psychiatry. Aug, 2010  |  Pubmed ID: 20712726

This article aims to describe the Hong Kong experience in developing and implementing an early psychosis programme.

Naming Psychosis: the Hong Kong Experience

Early Intervention in Psychiatry. Nov, 2010  |  Pubmed ID: 20977682

Schizophrenia translates in Chinese as 'Mind Split Disease' which is heavily stigmatizing. The narrow conceptualization for schizophrenia alone was insufficient, in the context of early detection and intervention for psychosis. The need for an effective Chinese translation for psychotic disorders was imminent upon the launch of the Early Assessment Service for Young People with Psychosis in Hong Kong, where public awareness strategies had to be built upon effective communication of the disorder.

The Impact of Anxiety-inducing Distraction on Cognitive Performance: a Combined Brain Imaging and Personality Investigation

PloS One. 2010  |  Pubmed ID: 21152391

Previous investigations revealed that the impact of task-irrelevant emotional distraction on ongoing goal-oriented cognitive processing is linked to opposite patterns of activation in emotional and perceptual vs. cognitive control/executive brain regions. However, little is known about the role of individual variations in these responses. The present study investigated the effect of trait anxiety on the neural responses mediating the impact of transient anxiety-inducing task-irrelevant distraction on cognitive performance, and on the neural correlates of coping with such distraction. We investigated whether activity in the brain regions sensitive to emotional distraction would show dissociable patterns of co-variation with measures indexing individual variations in trait anxiety and cognitive performance.

Executive Function in First-episode Schizophrenia: a Three-year Longitudinal Study of an Ecologically Valid Test

Schizophrenia Research. Mar, 2011  |  Pubmed ID: 21194894

Executive function impairment is a key cognitive deficit in schizophrenia. However, traditional neuropsychological tests of executive function may not be sensitive enough to capture the everyday dysexecutive problems experienced by patients. Additionally, existing literature has been inconsistent about longitudinal changes of executive functions in schizophrenia. The present study focuses on examining the longitudinal change of executive functions in schizophrenia using the Modified Six Elements Test (MSET) that was developed based on the Supervisory Attentional System model and shown to be sensitive to everyday dysexecutive problems. In the present study, MSET performance was assessed in 31 medication-naïve first-episode schizophrenic patients at four times over a period of three years, while the 31 normal controls were assessed once. Patients demonstrated impairment in MSET as compared to controls. Importantly, the MSET impairment persisted from the medication-naïve state to clinical stabilization and the three years following the first psychotic episode though patients improved in a conventional executive test (Modified Wisconsin Card Sorting Test). Performance was not related to intelligence, educational level, symptom changes, age-of-onset, or duration of untreated psychosis. Better MSET performance at medication-naïve state predicted improvement in negative and positive symptoms over the three-year period. These findings may suggest that MSET impairment is a primary deficit in schizophrenia that occurs early in the course of the illness and remains stable irrespective of clinical state for at least three years following the first episode of schizophrenia.

Gender Differences in Patients Presenting with First-episode Psychosis in Hong Kong: a Three-year Follow Up Study

The Australian and New Zealand Journal of Psychiatry. Mar, 2011  |  Pubmed ID: 21261552

The aim of the current study was to investigate gender differences with respect to pre-treatment characteristics, clinical presentation, service utilization and functional outcome in patients presenting with first-episode psychosis.

Perceptions of Relapse Risks Following First-episode Psychosis and Attitudes Towards Maintenance Medication: a Comparison Between Nursing and Social Work Professionals

Early Intervention in Psychiatry. Nov, 2011  |  Pubmed ID: 21521490

Existing clinical guidelines have not yet identified an optimal duration of maintenance antipsychotic drug treatment for stable, remitted first-episode psychosis patients. This study compares the perception of relapse risk and attitudes towards maintenance medication among professionals in nursing and social work fields who have direct clinical experience with first-episode psychosis patients. We explore a perception model that identifies the decision-making factors in the clinical dilemma between relapse and maintenance.

Three-year Outcome of Phase-specific Early Intervention for First-episode Psychosis: a Cohort Study in Hong Kong

Early Intervention in Psychiatry. Nov, 2011  |  Pubmed ID: 21726421

Although phase-specific early intervention for first-episode psychosis has been implemented in many different parts of the world, limited medium-term outcome data are available in non-Western populations with relatively low mental health resources. The study aimed to determine the effectiveness of phase-specific early intervention in first-episode psychosis.

Persistent Negative Symptoms in First-episode Schizophrenia: a Prospective Three-year Follow-up Study

Schizophrenia Research. Dec, 2011  |  Pubmed ID: 21968080

Negative symptoms are a core feature of schizophrenia. The evolution and trajectory of primary negative symptoms were under-studied. We aimed at evaluating the prevalence and stability of primary negative symptoms, and factors associated with persistent primary negative symptoms in a first-episode sample.

Screening and Assessing Ideas and Delusions of Reference Using a Semi-structured Interview Scale: A Validation Study of the Ideas of Reference Interview Scale (IRIS) in Early Psychosis Patients

Schizophrenia Research. Jan, 2012  |  Pubmed ID: 22244183

BACKGROUND: Ideas and delusions of reference (IOR/DOR) are an important but underrecognized research target. Difficulty in their reliable assessment has been a barrier. A screening and assessment tool incorporating a self-information processing framework, the Ideas of Reference Interview Scale (IRIS), was developed and validated in patients with early psychosis. METHODS: Comprehensive review of IOR/DOR phenomena in the literature and pilot interviews were conducted for scale item development. Self-referential themes were summarized into 15 items. A consecutive sample of 137 outpatients with early psychosis was interviewed using IRIS. Their IOR/DOR experiences were also rated independently by clinicians on the Scale for the Assessment of Positive Symptoms (SAPS) and self-rated using the IOR subscale on the Schizotypal Personality Questionnaire (SPQ). Inter-rater reliability of IRIS was examined in a subsample of 15 participants. RESULTS: IRIS demonstrated good internal consistency (Cronbach's alpha 0.80), inter-rater reliability (intraclass correlation coefficient 0.95), and divergent validity with other symptoms. IRIS correlated satisfactorily with the IOR/DOR item or subscale on SAPS and SPQ (Spearman's rho=0.71 and 0.47, respectively). DISCUSSION: IRIS provided a reliable high-resolution tool for progressing single-symptom research into IOR/DOR, a potential target feature of schizophrenia. The scale allows future investigation into self-referential processing and detailed phenomenological comparison in different clinical, subclinical, and healthy populations.

Clinical and Cognitive Correlates of Insight in First-episode Schizophrenia

Schizophrenia Research. Jan, 2012  |  Pubmed ID: 22245186

This study aims to explore the relationship between clinical symptoms and cognitive functions with different insight dimensions in patients with first-episode schizophrenia. Seventy-nine patients were assessed following six months of treatment. Insight was assessed using the abridged version of Scale of Unawareness of Mental Disorder (SUMD). Symptoms were assessed using Positive and Negative Syndrome Scale (PANSS). Cognitive functions were assessed using the Modified Wisconsin Card Sorting Test (MWCST), semantic verbal fluency and the letter-number sequencing (LNS) test from the Wechsler Adult Intelligence Scale (WAIS). Positive, negative and disorganized symptoms were found to be correlated with overall insight and all three general insight dimensions. Only perseverative errors and categories completed of MWCST were correlated with overall insight. Perseverative errors and non-perseverative errors of MWCST were correlated with the awareness of medication effects; perseverative errors of MWCST were also correlated with the awareness of social consequence of the illness. These support the link between poor insight and impaired executive function particularly measured by MWCST. The specific correlation of cognitive functions and different dimensions of insight suggests different underlying mechanism within each dimension of insight. The combined model of symptomatology and cognitive function explained 20.6% to 36.4% of the variance in the lack of insight within the different dimensions. The modest combined relationship of clinical and cognitive function with insight suggests that the exploration of other models in relationship to different insight dimensions is important.

Executive Function in First-episode Schizophrenia: A Three-year Prospective Study of the Hayling Sentence Completion Test

Schizophrenia Research. Jan, 2012  |  Pubmed ID: 22260962

In recent decade, deficits in the mechanism of Supervisory Attentional System (SAS) have become increasingly influential in explaining the nature of dysexecutive syndrome experienced by schizophrenic patients. The SAS model is characterized by having a detailed sub-classification of specific executive function components, among which semantic inhibition has been investigated using the Hayling Sentence Completion Test (HSCT). Several studies thus far have indicated that schizophrenic patients show impairment in HSCT performance. However, HSCT data concerning first-episode patients is still scarce. Besides, as previous HSCT studies were all cross-sectional in nature, they were not able to assess changes in HSCT performance over time. In order to address the paucity of knowledge about the longitudinal trajectories and correlates of semantic inhibition deficits in early schizophrenia, this paper reports a three-year prospective study of HSCT performance in medication-naïve, first-episode patients with schizophrenia-spectrum disorders. HSCT performance was assessed in 34 patients at four times over a period of three years, while the 34 healthy controls were assessed once. We found that medication-naïve patients demonstrated impairment in the inhibition condition in HSCT as compared to controls, but not in the initiation condition. Such HSCT impairment gradually improved in the three years following the first psychotic episode; however, HSCT performance did not predict improvement in negative or positive symptoms over the three-year period. The present findings suggest that semantic inhibition impairment is a specific deficit in schizophrenia that may require early intervention efforts, with the goal of facilitating more successful verbal communication and thereby better interpersonal functioning.

Prediction of Remission and Recovery in Young People Presenting with First-episode Psychosis in Hong Kong: A 3-year Follow-up Study

The Australian and New Zealand Journal of Psychiatry. Feb, 2012  |  Pubmed ID: 22311526

Objective: The aim of the current study was to investigate the rates and predictors of symptomatic remission and recovery in patients presenting with first-episode psychosis 3 years after treatment initiation. Methods: Seven hundred participants aged 15-25 years consecutively enrolled in a territory-wide early intervention programme in Hong Kong from July 2001 to August 2003 fulfilled study inclusion criteria, with 539 completing 3-year follow-up. Baseline and follow-up variables were collected via systematic medical file review. The operational criteria for recovery were based on clinical definition incorporating both symptom and functional dimensions. Results: By the end of 3-year follow-up, 58.8% (n = 317) and 17.4% (n = 94) of participants met criteria for symptomatic remission and recovery, respectively. Around half (51.2%, n = 276) were not remitted either symptomatically or functionally in the last 12 months of follow-up. Of those who achieved sustained symptomatic remission, only 43.1% were also in functional remission. Patients in symptomatic remission had lower rate of admissions, shorter duration of hospitalisations and more favourable psychosocial functioning than non-remitted counterparts. Logistic regression analysis revealed that female sex, older age of onset of psychosis, shorter duration of untreated psychosis (DUP) and early symptom resolution predicted symptomatic remission at the end of follow-up. Higher educational attainment, superior baseline occupational status and shorter DUP were found to be predictive of recovery. Conclusion: In a large representative cohort of Chinese young people presenting with first-episode psychosis, although more than half achieved symptomatic remission 3 years after service entry, the rates of functional remission and recovery were low. More intensive psychosocial interventions may be required to further improve patients' functional outcome.