Motivational intervention to reduce cannabis use in young people with psychosis: a randomized controlled trial.

BACKGROUND: Cannabis use has a negative impact on psychosis. Studies are needed to explore the efficacy of psychological interventions to reduce cannabis use in psychosis. Our aim is to study the efficacy of a specific motivational intervention on young cannabis users suffering from psychosis. METHODS: Participants (aged less than 35 years) were randomly assigned to treatment as usual (TAU) alone, or treatment as usual plus motivational intervention (MI + TAU). TAU was comprehensive and included case management, early intervention and mobile team when needed. Assessments were completed at baseline and at 3, 6 and 12 months follow-up. RESULTS: Sixty-two participants (32 TAU and 30 MI + TAU) were included in the study. Cannabis use decreased in both groups at follow-up. Participants who received MI in addition to TAU displayed both a greater reduction in number of joints smoked per week and greater confidence to change cannabis use at 3 and 6 months follow-up, but differences between groups were nonsignificant at 12 months. CONCLUSIONS: MI is well accepted by patients suffering from psychosis and has a short-term impact on cannabis use when added to standard care. However, the differential effect was not maintained at 1-year follow-up. MI appears to be a useful active component to reduce cannabis use which should be integrated in routine clinical practice.

Genetic dysregulation of glutathione synthesis predicts alteration of plasma thiol redox status in schizophrenia.

Genetic studies have shown an association between schizophrenia and a GAG trinucleotide repeat (TNR) polymorphism in the catalytic subunit (GCLC) of the glutamate cysteine ligase (GCL), the key enzyme for glutathione (GSH) synthesis. The present study was aimed at analyzing the influence of a GSH dysregulation of genetic origin on plasma thiols (total cysteine, homocysteine, and cysteine-glycine) and other free amino acid levels as well as fibroblast cultures GSH levels. Plasma thiols levels were also compared between patients and controls. As compared with patients with a low-risk GCLC GAG TNR genotype, patients with a high-risk genotype, having an impaired GSH synthesis, displayed a decrease of fibroblast GSH and plasma total cysteine levels, and an increase of the oxidized form of cysteine (cystine) content. Increased levels of plasma free serine, glutamine, citrulline, and arginine were also observed in the high-risk genotype. Taken together, the high-risk genotypes were associated with a subgroup of schizophrenia characterized by altered plasma thiols and free amino acid levels that reflect a dysregulation of redox control and an increased susceptibility to oxidative stress. This altered pattern potentially contributes to the development of a biomarker profile useful for early diagnosis and monitoring the effectiveness of novel drugs targeting redox dysregulation in schizophrenia.

Encoding dysfunctions in a dynamic-static paradigm for visuospatial working memory in first-episode psychosis patients: a 2-year follow-up study.

AIM: To investigate static and dynamic visuospatial working memory (VSWM) processes in first-episode psychosis (FEP) patients and explore the validity of such measures as specific trait markers of schizophrenia. METHODS: Twenty FEP patients and 20 age-, sex-, laterality- and education-matched controls carried out a dynamic and static VSWM paradigm. At 2-year follow up 13 patients met Diagnostic and Statistical Manual (of Mental Health Disorders)--Fourth Edition (DSM-IV) criteria for schizophrenia, 1 for bipolar disorder, 1 for brief psychotic episode and 5 for schizotypal personality disorder. RESULTS: Compared with controls, the 20 FEP patients showed severe impairment in the dynamic VSWM condition but much less impairment in the static condition. No specific bias in stimulus selection was detected in the two tasks. Two-year follow-up evaluations suggested poorer baseline scores on the dynamic task clearly differentiated the 13 FEP patients who developed schizophrenia from the seven who did not. CONCLUSIONS: Results suggest deficits in VSWM in FEP patients. Specific exploratory analyses further suggest that deficit in monitoring-manipulation VSWM processes, especially involved in our dynamic VSWM task, can be a reliable marker of schizophrenia.

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.

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.

Visuo-spatial processing in a dynamic and a static working memory paradigm in schizophrenia.

Recent findings suggest that the visuo-spatial sketchpad (VSSP) may be divided into two sub-components processing dynamic or static visual information. This model may be useful to elucidate the confusion of data concerning the functioning of the VSSP in schizophrenia. The present study examined patients with schizophrenia and matched controls in a new working memory paradigm involving dynamic (the Ball Flight Task - BFT) or static (the Static Pattern Task - SPT) visual stimuli. In the BFT, the responses of the patients were apparently based on the retention of the last set of segments of the perceived trajectory, whereas control subjects relied on a more global strategy. We assume that the patients' performances are the result of a reduced capacity in chunking visual information since they relied mainly on the retention of the last set of segments. This assumption is confirmed by the poor performance of the patients in the static task (SPT), which requires a combination of stimulus components into object representations. We assume that the static/dynamic distinction may help us to understand the VSSP deficits in schizophrenia. This distinction also raises questions about the hypothesis that visuo-spatial working memory can simply be dissociated into visual and spatial sub-components.

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.

Rapid brain discrimination of sounds of objects.

Electrical neuroimaging in humans identified the speed and spatiotemporal brain mechanism whereby sounds of living and man-made objects are discriminated. Subjects performed an "oddball" target detection task, selectively responding to sounds of either living or man-made objects on alternating blocks, which were controlled for in their spectrogram and harmonics-to-noise ratios between categories. Analyses were conducted on 64-channel auditory evoked potentials (AEPs) from nontarget trials. Comparing responses to sounds of living versus man-made objects, these analyses tested for modulations in local AEP waveforms, global response strength, and the topography of the electric field at the scalp. In addition, the local autoregressive average distributed linear inverse solution was applied to periods of observed modulations. Just 70 ms after stimulus onset, a common network of brain regions within the auditory "what" processing stream responded more strongly to sounds of man-made versus living objects, with differential activity within the right temporal and left inferior frontal cortices. Over the 155-257 ms period, the duration of activity of a brain network, including bilateral temporal and premotor cortices, differed between categories of sounds. Responses to sounds of living objects peaked approximately 12 ms later and the activity of the brain network active over this period was prolonged relative to that in response to sounds of man-made objects. The earliest task-related effects were observed at approximately 100 ms poststimulus onset, placing an upper limit on the speed of cortical auditory object discrimination. These results provide critical temporal constraints on human auditory object recognition and semantic discrimination processes.

[Early intervention in psychotic disorders: which role for primary care practitioners?]. / Intervention précoce dans les troubles psychotiques: quel rôle pour les praticiens de premier recours?

The development of early intervention in psychotic disorders has allowed a more optimistic approach and the development of more adapted and more efficient treatments. Primary care practitioners are often the first professional contact for patients developing psychosis, but diagnostic difficulties and patients' reluctance to engage in treatment are often an obstacle to private practice treatment. It is therefore important to provide more information to primary care practitioners on specific characteristics of these disorders and about locally available treatment structures in order to allow them to suspect this relatively rare diagnosis, facilitate the collaboration with flexible and accessible specialist services, that ideally should provide home treatment, and to improve prognosis.

Event-related potentials and time course of the "other-race" face classification advantage.

Other-race faces are less accurately recognized than same race faces but classified faster by race. Using event-related potentials (ERPs), we captured the brain temporal dynamics of face classification by race processing performed by 12 Caucasian participants. As expected, participants were faster to classify by race Asian than Caucasian faces. ERPs results identified the occurrence of the other-race face classification advantage at around 240 ms, in a stage related to the processing of visual information at the semantic level. The elaboration of individual face structural representation, reflected in the N170 face-sensitive component, was insufficient to achieve this process. Altogether, these findings suggest that the lesser experience of other-race faces engender fewer semantic representations, which in turn accelerate their speed of processing.

The perception of minimal structures: performance on open and closed versions of visually presented Euclidean travelling salesperson problems.

The planar Euclidean version of the travelling salesperson problem (TSP) requires finding a tour of minimal length through a two-dimensional set of nodes. Despite the computational intractability of the TSP, people can produce rapid, near-optimal solutions to visually presented versions of such problems. To explain this, MacGregor et al (1999, Perception 28 1417-1428) have suggested that people use a global-to-local process, based on a perceptual tendency to organise stimuli into convex figures. We review the evidence for this idea and propose an alternative, local-to-global hypothesis, based on the detection of least distances between the nodes in an array. We present the results of an experiment in which we examined the relationships between three objective measures and performance measures of optimality and response uncertainty in tasks requiring participants to construct a closed tour or an open path. The data are not well accounted for by a process based on the convex hull. In contrast, results are generally consistent with a locally focused process based initially on the detection of nearest-neighbour clusters. Individual differences are interpreted in terms of a hierarchical process of constructing solutions, and the findings are related to a more general analysis of the role of nearest neighbours in the perception of structure and motion.

Vulnerability to schizophrenia: relevance of patients' subjective experience for empirical and clinical work.

Efforts are being made by clinicians and researchers to accurately delineate phenotypic traits of individuals at enhanced risk of schizophrenia. This issue is important for a better understanding of the etiopathogenic mechanisms of the disease and for the building up of programs of primary prevention. We suggest that disturbances of subjective experience, although difficult to operationalize, are an important-but until now neglected-core component of schizophrenia spectrum disorders. We advocate the development of valid and reliable instruments in order to allow the assessment of basic symptoms and disturbances of Self-experience. Delineation of vulnerability to schizophrenia cannot rely solely on neuropsychological and neurophysiological data, as prevention programs will be performed mainly by clinicians.

Reduced P300 amplitude in a visual recognition task in patients with schizophrenia.

We studied top-down visual processes in schizophrenia by analyzing visual event-related potentials (ERPs) during a gestalt recognition task, after subjects (patients with schizophrenia, n = 10; controls, n = 14) were trained to perceive three different geometrical shapes. Recognition performance of patients was poorer under both the figure and the nonfigure conditions then that of normal controls. ERPs analysis indicated that P300 amplitudes of the patients were significantly smaller than those of controls during correct figure detection trials. Moreover, topographical analysis of the differences in ERPs during the figure vs the nonfigure condition showed an earlier, more positive and more widely distributed P300 in controls than in patients with schizophrenia. Our study supports the misconnection hypothesis of schizophrenia and highlights the difficulty of the patients to refer to previous experience in order to filter incoming information. In a visual recognition task, this misconnection syndrome might induce a failure to integrate information stored in the frontal and prefrontal sites with incoming stimuli.

Performance and reaction times in monaural localization of first names in the horizontal plane.

Many studies have been conducted to measure monaural azimuthal sound localization performance with different sounds varying in frequency and complexity, but few have used linguistic stimuli. The present experimental design used subjects' first names in a monaural azimuthal localization task. Analysis of response accuracy showed that subjects are not more accurate in localizing their own first name than in localizing other first names and that there was no significant advantage of one ear over another. Reaction times were shorter when the subjects localized their own first name than when they localized any other first names and there was no significant ear advantage, but localizing other first names took more time with the right than with the left ear. All stimuli were better and more quickly localized on the side of the open ear, and there was no difference in acuity or velocity of localization with the two different speaker voices used. These results suggest that first names are processed through the controlateral auditory pathway and can be analyzed in the right hemisphere.