Alain Labelle

A Canadian multicenter placebo-controlled study of fixed doses of risperidone and haloperidol in the treatment of chronic schizophrenic patients.

In a double-blind study, 135 inpatients with a diagnosis of chronic schizophrenia were randomly assigned to 8 weeks of treatment with one of six parallel treatments: risperidone (a new central 5-hydroxytryptamine2 and dopamine D2 antagonist), 2, 6, 10, 16 mg/day; haloperidol, 20 mg/day; or placebo, after a single-blind placebo washout period. Doses were increased in fixed increments up to a fixed maintenance dose reached after 1 week. On the Clinical Global Impression-Severity of Illness and Improvement, all active medications were superior to placebo except for risperidone (2 mg) on the Clinical Global Impression-Improvement. On the total Positive and Negative Syndrome Scale (PANSS) score and positive subscale, superiority to placebo was observed for all treatment groups except for haloperidol and risperidone (2 mg), which tended to be superior to placebo on total PANSS and the positive subscale, respectively. On the PANSS negative subscale, only risperidone (6 mg/day) was significantly better than placebo. Risperidone (6 mg) was superior to haloperidol on the total PANSS, General Psychopathology, and Brief Psychiatric Rating Scale subscales. Although there was a linear increase in parkinsonism with increasing risperidone dosage, there were no statistically significant differences between risperidone (2, 6, and 16 mg/day) and placebo. At doses of 6 to 16 mg, risperidone displayed a marked antidyskinetic effect compared with placebo. This effect was more pronounced in patients with severe dyskinesia. By contrast, haloperidol produced significantly more parkinsonism than placebo and risperidone (2, 6 and 16 mg), with no effect on tardive dyskinesia. These data suggest that risperidone, at the optimal therapeutic dose of 6 mg/day, produced significant improvement in both positive and negative symptoms without an increase in drug-induced parkinsonian symptoms and with a significant beneficial effect on tardive dyskinesia.

Quantitative EEG in schizophrenia and in response to acute and chronic clozapine treatment.

Topographic quantitative electroencephalographic (EEG) power and frequency indices were collected in 17 treatment refractory, DSM-III diagnosed schizophrenic patients, before and after acute (single dose) and chronic (six weeks) clozapine treatment, as well as in 17 healthy volunteers. Prior to treatment, patients exhibited greater overall absolute theta power, slower mean alpha frequency and elevated absolute delta and total power in anterior regions. Acute dosing increased total spectrum power globally, slow wave power posteriorally, mean alpha frequency and beta power anteriorally and decreased alpha power posteriorally. Six weeks of clozapine treatment significantly reduced clinical ratings of positive and negative symptoms as well as symptoms of global psychopathology. Chronic treatment resulted in EEG slowing as shown by decreases in relative alpha power, mean beta/total spectrum frequency and by widespread increases in absolute total and delta/theta power. The preliminary findings suggest that brain electric profiling may be a promising tool for assessing and understanding the central impact of pharmacotherapeutic interventions in schizophrenia.

Age of onset in familial and sporadic schizophrenia.

We have studied the gender and family history differences with regard to age of onset of schizophrenia. These differences have often been viewed as an important clue to the aetiology of the illness. Patients from three centres in Europe and Canada were included in the study. A sample of 1089 subjects was categorized according to the subjects sex, family history of schizophrenia, and the centre. The principal statistical method was analysis of variance. Patients with no family history of schizophrenia had a consistently higher average age of onset. This effect was seen in both male and female subjects across all three groups. These results support the relationship between familial risk and early onset, but no interaction of gender and family history was found.

Risperidone in the treatment of pervasive developmental disorder.

Elevated concentrations of blood serotonin have been documented in autistic children and mentally retarded adults. Antiserotonergic pharmacotherapy has been partially effective in treating a subgroup of children with autistic disorder. Therefore, the possibility is raised that an antiserotonergic treatment may be of value to adult psychiatric patients with a history of pervasive developmental disorder. Two such cases are described where the patients underwent psychiatric and neuropsychological examination before and after treatment with risperidone, a potent 5-HT2 antagonist with additional D2 antagonistic properties. Particular improvements were documented in both patients, despite long histories of cognitive compromise and high likelihood of damage to the central nervous system.

The right profile: mismatch negativity in schizophrenia with and without auditory hallucinations as measured by a multi-feature paradigm.

OBJECTIVE To examine pre-attentive acoustic change detection in schizophrenia patients with and without auditory hallucinations via mismatch negativity (MMN) extracted from a multi-feature paradigm. METHODS This study examined the electroencephalograph (EEG)-derived MMN, recorded across 32 sites, in 12 hallucinating patients (HPs) with schizophrenia, 12 non-hallucinating patients (NPs) with schizophrenia and 12 healthy controls (HCs). MMN was recorded in response to a multi-feature MMN paradigm [Näätänen, R., et al., 2004. The mismatch negativity (MMN): towards the optimal paradigm. Clin. Neurophys. 115, 140-144] which employs frequency, duration, intensity, location and gap deviants. Differences in source localization were probed using standardized low resolution brain electromagnetic tomography (sLORETA). RESULTS HPs showed significantly smaller MMNs to duration deviants compared to HCs and NPs, as well as smaller MMNs to intensity deviants compared to HCs. Regionalized differences between HCs and each of the patient groups were observed in response to frequency deviants. There were no significant group effects for location or gap deviants, or for MMN latency. Source localization using sLORETA showed no significant differences in MMN generator location across groups for any of the deviant stimuli. CONCLUSIONS The often-reported robust MMN deficit to duration deviants may be specific to schizophrenia patients afflicted with auditory hallucinations. Furthermore, by using symptom-specific groups, novel deficits of pre-attentive auditory processing, such as that observed to intensity deviants in HPs, may be revealed. SIGNIFICANCE The differential responding observed between both groups of patients with schizophrenia has implications for automatic processing within the auditory cortex of hallucinating patients and suggests that care must be taken when recruiting participants in studies involving schizophrenia to ensure consistent, replicable results.

Double-blind, placebo-controlled comparison of the efficacy of sertraline as treatment for a major depressive episode in patients with remitted schizophrenia

The effectiveness of selective serotonin reuptake inhibitors for depression in remitted schizophrenia has not been clearly demonstrated. A randomized, double-blind, prospective placebo-controlled study was performed of 48 subjects meeting DSM-IV criteria for both schizophrenia in remission and for a major depressive episode. Twenty-seven patients were randomized to placebo and 21 to sertraline. All subjects had a 1-week anticholinergic phase before randomization. The treatment duration was 6 weeks. Sertraline was started at 50 mg/day; this could be increased to 100 mg after 4 weeks for an inadequate response. There were no statistically significant differences in symptoms between the two groups at randomization. There were no differences in outcome between treatment groups. In both groups, between 40% and 50% of subjects showed a 50% reduction in depression score. This study does not provide support for the efficacy of sertraline in the treatment of depression in remitted schizophrenia. The small sample size limits the strength of the conclusions that can be drawn from this study. The study design called for a sample size of 96 on the basis of an expected placebo response rate of 30%. Recruitment for the study was difficult because of the placebo design. The placebo response was 50%. Clinicians and patients underestimate the strength of the placebo response and may overestimate the risk of participating in such a study. Testing the efficacy of widely accepted but poorly evaluated treatments should be a research priority. Future studies require a larger sample size and longer duration of treatment.

Neuropsychological change in schizophrenia after 6 weeks of clozapine

Neuropsychological change after 6weeks of clozapine treatment was examined in 18 treatment-refractory patients to test anticipated domain-specific cognitive improvements. The first aim of this study was to test the assumption that increased homogeneity of sample and treatment would yield an experimental design with sufficient sensitivity to detect general intellectual changes with clozapine that were not apparent in one previous investigation. The second aim was to test predictions derived from a domain-specific review of all other investigations with clozapine suggesting salient gains on tests sensitive to motor and mental speed, visual spatial manipulation, and new learning of verbal material. The results showed that the comprehensive neuropsychological test battery was sensitive to general cognitive changes with clozapine, and supported the hypothesized domain-specific gains on tests of motor and mental speed, visual spatial manipulation and new verbal learning. Novel gains were also apparent on tests of new learning with nonverbal material. The results are discussed in relation to aspects of experimental design necessary for the evaluation of prospective medication-induced changes in cognitive skill, particularly in future investigations designed to differentiate between second-generation antipsychotic medications.

DRD3 and DAT1 genes in schizophrenia: an association study.

OBJECTIVE To investigate the role of the dopamine receptor 3 (DRD3) and transporter 1 (DAT1) genes in schizophrenia or in modulating its phenotype. METHODS a Ser9Gly polymorphism in codon 9 of the DRD3 and a VNTR polymorphism in the DAT1genes were examined in two groups of schizophrenic patients, one of excellent neuroleptic responders (N=42) and one of nonresponders (N=64). A group of healthy volunteers screened for major psychiatric disorders was also included (N=89). In addition, age at onset of psychotic symptoms, attention performance and family loading for schizophrenia spectrum disorders were compared between patients with different genotypes in the DRD3 and DAT1 genes. RESULTS No significant differences in the allelic distribution of the DRD3 and DAT1 polymorphisms were detected between schizophrenic patients and controls. A trend toward an excess of DRD3 genotype Gly/Gly was observed in neuroleptic nonresponder schizophrenic patients compared to controls (chi(2)=3. 30, df=1, p=0.07). No significant differences in age at onset of psychotic symptoms, attention task performance or family loading for schizophrenia spectrum disorders were observed between groups with different DRD3 and DAT1 genotypes. CONCLUSION These results do not support the role of either of these genes in increasing susceptibility to schizophrenia or in modulating its phenotype in the studied population.

Neuropsychological impairments in neuroleptic-responder vs. -nonresponder schizophrenic patients and healthy volunteers.

To determine whether two groups of schizophrenic patients representing the two extremes of the neuroleptic response-spectrum (consistent responders vs. consistent nonresponders) differ with respect to their neuropsychological profile. Neuroleptic-responder (R; n=36) and -nonresponder (NR; n=39) schizophrenic patients were recruited according to a priori defined criteria of responsiveness to typical neuroleptics. Seven neuropsychological domains were assessed and compared between groups: attention-vigilance, abstraction-flexibility, spatial organization, visual-motor processing, visual memory, verbal abilities, and verbal memory and learning. All measures were standardized using the scores of 36 healthy volunteers. NR schizophrenic patients performed worse in all neuropsychological domains compared to normal controls and R schizophrenic patients. However, only performances on visual memory, verbal abilities, and verbal memory and learning were significantly poorer in NR compared to R patients. Only the latter domain significantly differentiated NR patients from the other two groups. R patients performed at an intermediate level in all domains. This report of differences in neuropsychological profile between neuroleptic-responder and -nonresponder schizophrenic patients adds to the growing evidence supporting the value of distinguishing schizophrenic patients on the basis of their therapeutic response to neuroleptics.

Analysis of 14 CAG repeat-containing genes in schizophrenia.

Recently, it has been suggested that trinucleotide repeat-containing genes may be involved in the etiology of schizophrenia. This study was aimed at investigating putative associations between allelic variants or expansions of CAG repeat-containing genes (CAGrCG) and schizophrenia or its variability with respect to responsiveness to conventional neuroleptics. CAG repeat allelic variants of 14 expressed sequences were compared among three groups of subjects: neuroleptic-responder (R; n = 43) and neuroleptic-nonresponder (NR; n = 63) schizophrenic patients, and a control group (C; n = 122). No CAG expansions, in the range of those observed in neurodegenerative diseases, were identified in these 14 expressed sequences. The sizes of CAG repeat for the hGT1 gene were marginally different among the three groups of subjects (Kruskal-Wallis H (2, 456) = 10.48, Bonferroni corrected P = 0.047). Comparisons among the different groups indicated that neuroleptic responders have shorter alleles compared to controls (Mann-Whitney adjusted Z = -3.23, P = 0.0012). NR patients were not different from controls. These preliminary results suggest that the hGT1 gene, or a gene in its vicinity, may be involved in the etiology of schizophrenia or in modifying the disease phenotype with regard to outcome and/or neuroleptic responsiveness. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:694-699, 1999.