CATIE for clinicians.
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Antipsychotic Agents↗
Biomedical subjects
R Kerwin
Publications and source records attributed to R Kerwin.
Randomised controlled trials of conventional antipsychotic versus new atypical drugs, and new atypical drugs versus clozapine, in people with schizophrenia responding poorly to, or intolerant of, current drug treatment.
OBJECTIVES: To determine the clinical and cost-effectiveness of different classes of antipsychotic drug treatment in people with schizophrenia responding inadequately to, or having unacceptable side-effects from, their current medication. DESIGN: Two pragmatic, randomised controlled trials (RCTs) were undertaken. The first RCT (band 1) compared the class of older, inexpensive conventional drugs with the class of new atypical drugs in people with schizophrenic disorders, whose current antipsychotic drug treatment was being changed either because of inadequate clinical response or owing to side-effects. The second RCT (band 2) compared the new (non-clozapine) atypical drugs with clozapine in people whose medication was being changed because of poor clinical response to two or more antipsychotic drugs. Both RCTs were four-centre trials with concealed randomisation and three follow-up assessments over 1 year, blind to treatment. SETTING: Adult mental health settings in England. PARTICIPANTS: In total, 227 participants aged 18-65 years (40% of the planned sample) were randomised to band 1 and 136 (98% of the planned sample) to band 2. INTERVENTIONS: Participants were randomised to a class of drug. The managing clinician selected the individual drug within that class, except for the clozapine arm in band 2. The new atypical drugs included risperidone, olanzapine, quetiapine and amisulpride. The conventional drugs included older drugs, including depot preparations. As in routine practice, clinicians and participants were aware of the identity of the prescribed drug, but clinicians were asked to keep their participating patient on the randomised medication for at least the first 12 weeks. If the medication needed to be changed, the clinician was asked to prescribe another drug within the same class, if possible. MAIN OUTCOME MEASURES: The primary outcome was the Quality of Life Scale (QLS). Secondary clinical outcomes included symptoms [Positive and Negative Syndrome Scale (PANSS)], side-effects and participant satisfaction. Economic outcomes were costs of health and social care and a utility measure. RESULTS: Recruitment to band 1 was less than anticipated (40%) and diminished over the trial. This appeared largely due to loss of perceived clinical equipoise (clinicians progressively becoming more convinced of the superiority of new atypicals). Good follow-up rates and a higher than expected correlation between QLS score at baseline and at follow-up meant that the sample as recruited had 75% power to detect a difference in QLS score of 5 points between the two treatment arms at 52 weeks. The recruitment to band 2 was approximately as planned. Follow-up assessments were completed at week 52 in 81% of band 1 and 87% of band 2 participants. Band 1 data showed that, on the QLS and symptom measures, those participants in the conventional arm tended towards greater improvements. This suggests that the failure to find the predicted advantage for new atypicals was not due to inadequate recruitment and statistical power in this sample. Participants reported no clear preference for either class of drug. There were no statistically significant differential outcomes for participants entering band 1 for reasons of treatment intolerance to those entering because of broadly defined treatment resistance. Net costs over the year varied widely, with a mean of 18,850 pounds sterling in the conventional drug group and 20,123 pounds sterling in the new atypical group, not a statistically significant difference. Of these costs, 2.1% and 3.8% were due to antipsychotic drug costs in the conventional and atypical group, respectively. There was a trend towards participants in the conventional drug group scoring more highly on the utility measure at 1 year. The results for band 2 showed an advantage for commencing clozapine in quality of life (QLS) at trend level (p = 0.08) and in symptoms (PANSS), which was statistically significant (p = 0.01), at 1 year. Clozapine showed approximately a 5-point advantage on PANSS total score and a trend towards having fewer total extrapyramidal side-effects. Participants reported at 12 weeks that their mental health was significantly better with clozapine than with new atypicals (p < 0.05). Net costs of care varied widely, but were higher than in band 1, with a mean of 33,800 pounds sterling in the clozapine group and 28,400 pounds sterling in the new atypical group. Of these costs, 4.0% and 3.3%, respectively, were due to antipsychotic drug costs. The increased costs in the clozapine group appeared to reflect the licensing requirement for inpatient admission for commencing the drug. There was a trend towards higher mean participant utility scores in the clozapine group. CONCLUSIONS: For band 1, there is no disadvantage in terms of quality of life and symptoms, or associated costs of care, over 1 year in commencing conventional antipsychotic drugs rather than new atypical drugs. Conventional drugs were associated with non-significantly better outcomes and lower costs. Drug costs represented a small proportion of the overall costs of care (<5%). For band 2, there is a statistically significant advantage in terms of symptoms but not quality of life over 1 year in commencing clozapine rather than new atypical drugs, but with increased associated costs of care. The results suggest that conventional antipsychotic drugs, which are substantially cheaper, still have a place in the treatment of patients unresponsive to, or intolerant of, current medication. Further analyses of this data set are planned and further research is recommended into areas such as current antipsychotic treatment guidance, valid measures of utility in serious mental illness, low-dose 'conventional' treatment in first episode schizophrenia, QLS validity and determinants of QLS score in schizophrenia, and into the possible financial and other mechanisms of rewarding clinician participation in trials.
Adolescent↗
Amisulpride augmentation of clozapine: an open non-randomized study in patients with schizophrenia partially responsive to clozapine.
OBJECTIVE: Treatment options are very limited for individuals with schizophrenia resistant to clozapine. We tested the hypothesis that amisulpride augmentation would lead to an improvement in these patients. METHOD: This was an open non-randomized study. Thirty-three patients with sub-optimal response to clozapine were commenced on amisulpride in addition to clozapine. Clinical status was evaluated at baseline, 3 and 6 months using the Positive And Negative Syndrome Scale (PANSS), Scale for the Assessment of Negative Symptoms (SANS), Global Assessment Scale (GAS), Calgary Depression Scale, Calgary Anxiety Scale and various side effect rating scales. RESULTS: Twenty-eight subjects completed 6 months treatment on clozapine and amisulpride. There was a statistically significant improvement in the mean scores for PANSS, SANS and GAS at follow-up and no significant changes in side effect ratings. CONCLUSION: Co-administration of amisulpride, in a group of patients partially or non-responsive to clozapine, may lead to a substantial improvement in positive and negative symptoms, without worsening the side effect burden.
Amisulpride↗
Reduced expression of the muscarinic 1 receptor cortical subtype in schizophrenia.
The involvement of specific pathways mediated through muscarinic receptor activity has been widely implicated in schizophrenia. Extensive pharmacological evidence supports the systems role in mediating antipsychotic drug efficacy, while mounting physiological evidence demonstrates the presence of significant alterations to normal muscarinic receptor integrity in the disorder. The mechanisms that facilitate the systems involvement and their magnitude, however, remain poorly understood. We have proposed that alterations to normal muscarinic receptor expression exist in schizophrenia, and that these significantly influence the physiological changes often reported for the system amongst patients. In this study, we investigate this potential, and have selected to examine the muscarinic 1 receptor, which constitutes a major target for antipsychotic action and plays a conspicuous role in those regions central to the disorders pathophysiology. Using relative gene quantification, we measured post-mortem levels of steady-state cortical muscarinic 1 receptor cDNA in patients (N = 20) and unaffected controls (N = 20), and examined group differences in expression levels. Commensurate with our hypothesis, we observed significant reductions in muscarinic 1 receptor cDNA in our patient sample (F(1,37) = 4.73, P = 0.036) and have estimated this to constitute a 28% decrease compared to the control subjects (95% CI from 2 to 47%). These results provide evidence in support of altered muscarinic 1 receptor expression in schizophrenia, though further work is needed to corroborate these findings.
Aged↗
Preventing suicide.
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Antipsychotic Agents↗
Investigation of promoter variants of the histamine 1 and 2 receptors in schizophrenia and clozapine response.
We report the identification of four novel histamine 1 (H1-17-C/T, -974-C/A, -1023-A/G and -1536-G/C) and four novel histamine 2 promoter polymorphisms (H2-294-A/G, -592-A/G, -1018-G/A and -1077-G/A) which we have investigated for involvement in susceptibility to schizophrenia, and in clinical response to clozapine treatment. We identified a weak independent association between variants at the H1-1536-G/C locus and schizophrenia, where an excess of the H1-1536-C allele was observed amongst such patients (P = 0.036). However upon correction for multiple testing this relationship was no longer statistically significant. Similar investigation of the H2 receptor polymorphisms revealed association between genotype at the H2-1018-G/A locus and clinical response to clozapine treatment (P = 0.027), though upon correction for multiple testing this difference was no longer significant. We have concluded that the participation of these variants in the disorder is unlikely, particularly in view of their apparent lack of function and unlikely influence on receptor expression. However their nature alludes to the potential presence of other more important alterations further along these regions, where sequences encoding alternate promoters have recently been identified for each receptor that may yet be found to harbour such polymorphisms.
Antipsychotic Agents↗
Atypical antipsychotics in the treatment of schizophrenia. Paper underrates patients' experience of extrapyramidal symptoms.
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Antipsychotic Agents↗
Reduced glial cell density and neuronal size in the anterior cingulate cortex in major depressive disorder.
BACKGROUND: Glial cells are more numerous than neurons in the cortex and are crucial to neuronal function. There is evidence for reduced neuronal size in schizophrenia, with suggestive evidence for reduced glial cell density in mood disorders. In this investigation, we have simultaneously assessed glial cell density and neuronal density and size in the anterior cingulate cortex in schizophrenia, major depressive disorder, and bipolar disorder. METHODS: We examined tissue from area 24b of the supracallosal anterior cingulate cortex in 60 postmortem brain specimens from 4 groups of 15 subjects, as follows: major depressive disorder, schizophrenia, bipolar disorder, and normal controls. Glial cell density and neuronal size and density were examined in all subjects using the nucleator and the optical disector. RESULTS: Glial cell density (22%) (P =.004) and neuronal size (23%) (P =.01) were reduced in layer 6 in major depressive disorder compared with controls. There was some evidence for reduced glial density in layer 6 (20%) (P =.02) in schizophrenia compared with controls, before adjusting for multiple layerwise comparisons, but there were no significant changes in neuronal size. There was no evidence for differences in glial density or neuronal size in bipolar disorder compared with controls. Neuronal density was similar in all groups to that found in controls. CONCLUSION: These findings suggest that there is reduced frontal cortical glial cell density and neuronal size in major depressive disorder.
Adult↗
Increased dendritic MAP2 expression in the hippocampus in schizophrenia.
Microtubule associated proteins (MAPs) are central to the development of normal neuronal cytoarchitecture and have been reported to be altered in schizophrenia. In 12 schizophrenic (DSM-III-R criteria) and 12 control hippocampi, we estimated the MAP2 immunoreactive dendritic length using antibodies that recognize total MAP2 (MAP2-T), and a non-phosphorylated form of MAP2 (MAP2-NP). Within the corona ammonis (CA) subregions, and the subiculum, we estimated, for each antibody, the length of the immunoreactive dendritic arborisation using a stereological length estimation technique based on Bouffon's Needle principle and image analysis computer software. Controlling for the confounding effects of age and post-mortem delay, we have found an elevation in overall MAP2-NP immunoreactive dendritic length among schizophrenic subjects in the CA3 (F=5.9, p=0.03), CA2 (F=6.5, p=0.02), CA1 (F=8.3, p=0.01) and subicular (F=9.5, p=0.008) hippocampal subregions. Similar analyses of MAP2-T immunoreactive dendritic length demonstrated significant elevations in the CA1 (F=8.3, p=0.02), CA4 (F=4.9, p=0.04) and subicular (F=7.4, p=0.01) regions. The findings of this quantitative study of increased MAP2 immunoreactive dendritic arborisation in schizophrenia are most likely to reflect either an altered dendritic arborisation or a generalised increase in levels of MAP2 with the hippocampal pyramidal neurons. These findings add to the growing literature indicating the presence of synaptodendritic abnormalities in schizophrenia.
Adult↗
From pharmacological profiles to clinical outcomes.
The reformulated dopamine hypothesis of schizophrenia postulates that over-activity of dopaminergic neurones in limbic areas of the brain is responsible for the positive symptoms of the illness. At the same time, dopaminergic under-activity in the frontal cortex is thought to underlie the negative symptoms and cognitive impairment. In addition, it has emerged that classical dopaminergic D2 receptors comprise a family of several different subtypes of which D2 is widely distributed, whereas D3 and D4 are concentrated in limbic and cortical areas. Amisulpride selectively blocks D2 and D3 receptors but with preference for the latter. Amisulpride also has preferential activity at presynaptic rather than postsynaptic receptors. It was predicted therefore that amisulpride would alleviate both the under-activity in the frontal cortex and the over-activity in the limbic system. Amisulpride is also virtually free of activity at receptors for other neurotransmitters. This unique pharmacology is consistent with the therapeutic profile of amisulpride, which has been clearly demonstrated to control both the positive and negative symptoms of schizophrenia with equal efficacy as well as being well tolerated.
Amisulpride↗
Disturbance of Notch-1 and Wnt signalling proteins in neuroglial balloon cells and abnormal large neurons in focal cortical dysplasia in human cortex.
Determination of neuroglial cell fate and neural tube development during embryogenesis is influenced by the Notch/Wnt signalling pathway. We have studied the localisation of several proteins in the Wnt pathway in focal cortical dysplasia (FCD). This disorder, thought to be due to abnormalities of neuronal migration and differentiation, contains regions of morphologically normal neocortex interrupted by areas of neuronal laminar disorganisation, heterotopic white matter neurons, abnormal large neurons and balloon cells of uncertain histogenesis. We found that the subcellular distribution of several proteins involved in the Wnt pathway differed in regions of FCD from normal cortex, and that within the areas of FCD, the pattern varied with cellular phenotype. Thus, in balloon cells, elevated cytoplasmic levels of dishevelled (Dvl-1) protein were accompanied by an absence of Notch-1, increased adenomatous poliposis coli (APC), altered cytoplasmic beta-catenin, and reduced nuclear expression of beta-catenin. A contrasting pattern of expression was found in abnormal large neurons, which demonstrated elevated levels of Notch-1, and glycogen synthase kinase-3beta (GSK-3beta), and normal levels of APC. Our results are consistent with the notion that Wnt/Notch signalling influences neuroglial cell fate, and suggest that a perturbation of Wnt/Notch signalling may contribute to the neuropathology of FCD.
Adaptor Proteins, Signal Transducing↗
Neuronal nicotinic receptors in dementia with Lewy bodies and schizophrenia: alpha-bungarotoxin and nicotine binding in the thalamus.
Neuronal nicotinic receptors have been implicated in schizophrenia on the basis of the high incidence of tobacco smoking in patients, abnormalities in cytisine and alpha-bungarotoxin (alphaBGT) binding in the hippocampus, and linkage between auditory P50 deficits and the region of chromosome 15 coding the alpha7 subunit. In another disease associated with psychosis, dementia with Lewy bodies (DLB), in which visual hallucinations predominate, reductions in nicotine binding have been identified in various cortical and subcortical regions. We investigated both alphaBGT and nicotine binding autoradiographically in different thalamic nuclei in autopsy brain tissue from patients with schizophrenia and DLB. AlphaBGT binding in the reticular nucleus was moderately reduced (25%) in schizophrenia and more extensively reduced (50%) in DLB. There were no significant alterations in nicotine binding in schizophrenia, and in DLB, a trend towards moderate reductions in most nuclei reached significance in the lateral dorsal nucleus. It is concluded that widespread abnormalities of thalamic nicotine are not implicated in schizophrenia or DLB, but that reticular alphaBGT binding may be involved to a lesser and greater extent in the pathophysiology or psychopathology of both disorders.
Aged↗
Active monitoring of 12,760 clozapine recipients in the UK and Ireland. Beyond pharmacovigilance.
BACKGROUND: People prescribed clozapine for treatment-resistant schizophrenia have mandatory haematological monitoring through a case register for identifying reversible neutropenia. AIMS: To quantify risk factors for agranulocytosis in subjects receiving clozapine. METHOD: Data from 12,760 subjects registered to receive clozapine from January 1990 to April 1997 were analysed. Risk factors for agranulocytosis were quantified using a Cox proportional-hazards regression analysis. RESULTS: The risk for agranulocytosis in Asian subjects was 2.4 times that in Caucasians (P = 0.03). There was an age-related increase in risk of 53% per decade (P = 0.0001). CONCLUSIONS: The case register yielded valuable information for guiding research into the causes of the haematological reactions.
Adolescent↗
The answer lies within selective ligands and pharmacogenomics.
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Drug Overdose↗
Genetics of novel therapeutic targets in schizophrenia.
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Antipsychotic Agents↗
Abnormalities of Wnt signalling in schizophrenia--evidence for neurodevelopmental abnormality.
The Wnt signalling pathway is central to normal brain development in vertebrates and invertebrates and mediates cell fate determination, cell adhesion and cell proliferation. However, its relevance to disorders of cerebral development in man is untested. We evaluated the potential involvement of the Wnt signalling pathway in schizophrenia, a disorder of neurodevelopment origin in which alterations in neuronal lamination and orientation have been described. Using immunohistochemistry and semi-quantitative rating scales, we examined the distribution of two components of the Wnt signalling pathway, beta-catenin and gamma-catenin in the hippocampus and subiculum of 12 schizophrenic (DSMIIR criteria) and 14 control subjects. Both catenins were distributed as intraneuronal diffuse and/or ring shaped forms. The diffuse staining of both forms catenin were reduced in the CA3 and beta-catenin was also reduced in the CA4 hippocampal subregion among schizophrenic subjects. These alternations may represent the basis of the developmental brain abnormalities found in schizophrenia and would have functionally important consequences in the adult.
Adult↗
Alterations in hippocampal non-phosphorylated MAP2 protein expression in schizophrenia.
Microtubule-associated proteins (MAPs) are central to the development of normal neuronal cytoarchitecture and have been suggested in previous studies to be altered in schizophrenia. We investigated hippocampal phosphorylated and non-phosphorylated MAP2 expression in schizophrenia in relation to neuronal orientation and interneuronal distance. One paraffin embedded mid-hippocampal block was obtained from each of 8 schizophrenic and 11 control postmortem brains and immunohistochemistry for the phosphorylated and non-phosphorylated forms of MAP2 performed. Within the corona ammonis (CA) subregions and the subiculum, we assessed densitometry readings for non-phosphorylated MAP2-positive neurones (MAP2-NP), and counted the number of neurones immunopositive for phosphorylated MAP2 (MAP2-P). Using image analysis computer software we measured interneuronal distances and neuronal orientation. While there were no overall alterations in densitometric density of MAP2-NP neurones in any hippocampal subregions, we found a left-sided increase in densitometric density of MAP2-NP neurones within the subiculum (F = 8.740, P < 0.021), and the CA1 (F = 7.044, P < 0.033) of schizophrenic subjects which were unrelated to age, postmortem interval or neuroleptic exposure. There was no accompanying alteration of interneuronal distances, neuronal orientation. The findings support previous work demonstrating altered subicular MAP2 expression in schizophrenia and indicate that the finding may be lateralised. However, in contrast to previous investigations, we have demonstrated this alteration in MAP2 expression is due to an increase in the non-phosphorylated form of MAP2, rather than a decrease in total MAP2 expression. These findings suggest that cytoskeletal assembly is abnormal in schizophrenia and generate testable hypotheses regarding the developmental basis of the disorder.
Adult↗