Sertindole is associated with a low level of extrapyramidal symptoms in schizophrenic patients: Results of a phase III trial.

OBJECT: The objective of this double-blind, multicentre study was to evaluate four doses of sertindole and haloperidol 10 mg. METHOD: The 617 schizophrenic patients were randomized to receive sertindole 8, 16, 20 or 24 mg/day or haloperidol 10 mg/day. Patients were assessed for extrapyramidal symptoms (EPS) using the Simpson-Angus Scale (SAS) and Barnes Akathisia Scale (BAS), and for movement disorders using the Abnormal Involuntary Movement Scale (AIMS). RESULTS: Patients receiving haloperidol experienced significantly more EPS than patients receiving sertindole, supporting observations made in previous studies. The incidence of adverse events was similar for all doses of sertindole. SAS and BAS scores were significantly worse in the haloperidol group than in the sertindole groups. There were significantly greater increases in mean QT c interval in the sertindole groups than in the haloperidol group. Sertindole did not cause sedation. CONCLUSIONS: Sertindole is well tolerated and does not cause the debilitating EPS associated with traditional antipsychotic drugs. (Int J Psych Clin Pract 2000; 4:47-54).

Sertindole improves both the positive and negative symptoms of schizophrenia: Results of a phase III trial.

OBJECTS: This large multicentre, double-blind, randomized study was designed to evaluate four doses of sertindole and haloperidol 10 mg in the treatment of patients with DSM-III-R schizophrenia. METHOD: 617 patients were randomized, of whom 595 were included in an intention-to-treat analysis. 375 patients completed the study. Patients were randomized to receive sertindole 8 mg/day, sertindole 16 mg/day, sertindole 20 mg/day, sertindole 24 mg/day or haloperidol 10 mg/day for 56days. Efficacy was assessed through the changes in score on the Positive and Negative Syndrome Scale (PANSS), and the Clinical Global Impressions (CGI) scale. Improvement in all end-points was observed for all treatment groups. RESULTS: Sertindole 16 mg showed significantly greater efficacy against negative symptoms than haloperidol 10 mg. The optimal dose of sertindole was 16 mg/day. Sertindole 8 mg appeared to be suboptimal with respect to efficacy, and increasing the dose of sertindole above 20 mg did not appear to offer any additional benefit. Sertindole at all doses caused significantly fewer extrapyramidal symptoms than haloperidol. CONCLUSION: Sertindole is effective against positive and negative symptoms of schizophrenia within the dose range 12-24 mg daily, with an optimal starting dose of 16 mg daily. Efficacy is comparable to 10 mg of haloperidol with no difference in the time course of treatment response. The dose response relationship for efficacy with sertindole seems to plateau at about 16 mg daily with no demonstrable difference in increasing doses above this point. (Int J Psych Clin Pract 2000; 4:55-62).

Genetic association of the presenilin-1 regulatory region with early-onset Alzheimer's disease in a population-based sample.

Genetic association has been reported between a di-allelic polymorphism in intron 8 of presenilin-1 (PSEN1) and Alzheimer's disease (AD) in some studies but not in others. In a population-based series of 102 patients with early onset AD and 118 community controls we examined whether polymorphisms in linkage disequilibrium with intron8 of PSEN1 may explain the association. In addition to the intron 8 polymorphism (P = 0.05), a promoter polymorphism (P = 0.03) and the simple tandem repeat (STR) polymorphism D14S1028 located upstream of PSEN1 (P = 0.04) were found to be marginally significantly associated to AD. When excluding PSEN1 mutation cases (n = 6), the intron 8 association was explained by linkage disequilibrium to the dominant PSEN1 mutations. In the non-mutation cases, the weak associations between the polymorphisms in the regulatory region remained. Our study suggests that a polymorphism/mutation in the promoter or regulatory region of PSEN1 rather than the polymorphism in intron 8 of PSEN1 is associated with early onset AD.

Apolipoprotein E genotype, atherosclerosis, and cognitive decline: the Rotterdam Study.

The apolipoprotein E4 allele (APOE epsilon 4) and atherosclerosis are risk factors for cognitive decline. We investigated whether the effects of APOE epsilon 4 and atherosclerosis on cognitive decline are independent. A population-based follow-up study was performed on 838 subjects who were non-demented at baseline. The Mini Mental State Examination (MMSE) score at follow-up was studied as a function of APOE epsilon 4 and atherosclerosis. Mild, non-significant effects on the MMSE score were found for atherosclerosis in the absence of APOE epsilon 4 and for APOE epsilon 4 in the absence of atherosclerosis. APOE epsilon 4 carriers with two or more indicators of atherosclerosis positive, had a significantly lower MMSE score at follow-up (mean difference -0.7 points; 95% confidence interval -1.1 to -0.2) relative to non-APOE epsilon 4 carriers with no evidence of atherosclerosis. Our findings suggest that the consequences of APOE epsilon 4 and atherosclerosis are not independent, and that particularly APOE epsilon 4 carriers with atherosclerosis are at increased risk of cognitive decline.

The European Post-marketing Observational Serdolect (EPOS) Project: increasing our understanding of schizophrenia therapy.

Well-controlled clinical trials, although essential for registration purposes, often fail to reflect the real-life usage of a drug. Ultimately, it is how a new medicinal product is used in clinical practice, how it performs in everyday life and how the patient who takes it feels and functions that determine the real benefit: risk ratio of the drug. Such a prospective, referenced, cohort study of sertindole (Serdolect, H. Lundbeck A/S, Copenhagen, Denmark) in schizophrenia was initiated in 1997. Sertindole is a new limbic-selective antipsychotic agent which has recently received marketing authorization in several countries across Europe for the treatment of schizophrenia. The experience gained in around 2200 sertindole-treated patients in controlled clinical trials has enabled an optimal targeting of sertindole to those patient groups who will benefit most and who are least likely to experience adverse effects. The European Post-marketing Observational Serdolect (EPOS) project plans to recruit over 12000 patients in two cohorts in centres throughout Europe. The aims are to provide a full safety evaluation of sertindole under marketed conditions at the relevant clinical dosage and, further, to provide epidemiological data on the treatment of schizophrenia in Europe under usual clinical conditions. The study is currently the only one of its kind to be undertaken in schizophrenia, and will provide important new data for psychiatrists around the world.

Molecular genetic analysis of autosomal dominant cerebellar ataxia with retinal degeneration (ADCA type II) caused by CAG triplet repeat expansion.

Autosomal dominant cerebellar ataxia with retinal degeneration (ADCAII) was previously mapped by linkage analysis studies to chromosome 3p12-p21.1 (SCA7). Positional cloning efforts have recently identified a novel gene, SCA7 , containing a translated CAG repeat, expanded in SCA7 patients. We cloned the SCA7 gene from a yeast artificial chromosome (YAC) clone contig spanning the SCA7 candidate region. Using a combination of genomic sequencing and cosmid-based exon trapping, two expressed sequence tags were identified. Sequencing of the corresponding cDNA clones and RT-PCR analysis identified the full-length SCA7 cDNA. Together, our sequence data defined the intron/exon boundaries of the first two coding exons of the SCA7 gene, with the first exon containing the expanded CAG repeat. Further, sequence comparison with the published SCA7 cDNA identified one additional putative exon in the 5'-UTR region of the SCA7 gene. The SCA7 gene was mapped on the YAC contig in the 2.5 cM interval between D3S1600 and D3S1287. In one extended Belgian SCA7 pedigree the expanded alleles ranged from 38 to at least 55 repeats with allele lengths being inversely correlated with onset age of ADCAII symptoms. The SCA7 repeats increased in length in successive generations. Normal alleles had from four to 18 repeats, with 10 repeats being the most common allele.

Estimation of the genetic contribution of presenilin-1 and -2 mutations in a population-based study of presenile Alzheimer disease.

Two closely related genes, the presenilins ( PS ), located at chromosomes 14q24.3 and 1q42.1, have been identified for autosomal dominant Alzheimer disease (AD) with onset age below 65 years (presenile AD). We performed a systematic mutation analysis of all coding and 5'-non-coding exons of PS -1 and PS -2 in a population-based epidemiological series of 101 unrelated familial and sporadic presenile AD cases. The familial cases included 10 patients of autosomal dominant AD families sampled for linkage analysis studies. In all patients mutations in the amyloid precursor protein gene ( APP ) had previously been excluded. Four different PS -1 missense mutations were identified in six familial cases, two of which where autosomal dominant cases. Three mutations resulted in onset ages above 55 years, with one segregating in an autosomal dominant family with mean onset age 64 years (range 50-78 years). One PS -2 mutation was identified in a sporadic case with onset age 62 years. Our mutation data provided estimates for PS -1 and PS -2 mutation frequencies in presenile AD of 6 and 1% respectively. When family history was accounted for mutation frequencies for PS -1 were 9% in familial cases and 18% in autosomal dominant cases. Further, polymorphisms were detected in the promoter and the 5'-non-coding region of PS -1 and in intronic and exonic sequences of PS -2 that will be useful in genetic association studies.

EPOS: Increasing our understanding of the treatment of schizophrenia; Start of a prospective referenced cohort study of sertindole in clinical practice.

Sertindole is a new limbic-selective antipsychotic agent which has recently received marketing authorization in several countries across Europe for the treatment of schizophrenia. The experience gained in around 2200 patients treated with sertindole in controlled clinical trials has enabled optimal targeting of sertindole to those patient groups who will benefit most and who are least likely to experience adverse effects. Ultimately, it is how a new medicinal product is used in clinical practice, how it performs in everyday life, and how the patient who takes it feels and functions that determine the real benefit/risk ratio of a new medicinal product. The European Post-marketing Observational Serdolect® project (EPOS) is a post-marketing, referenced, observational, cohort, safety study in the treatment of schizophrenic patients initiated earlier this year. It is planned to recruit over 12 000 patients in two cohorts in centres throughout Europe. The aims are to provide a full safety evaluation of sertindole under marketed conditions at the relevant clinical dosage, and further, to provide epidemiological data on schizophrenic patients receiving sertindole or other treatment under the usual clinical conditions in Europe. At the moment, the study is the only one of its kind to be undertaken in schizophrenia and will provide important new data for psychiatrists around the world.

Molecular genetic analysis of familial early-onset Alzheimer's disease linked to chromosome 14q24.3.

Genetic linkage studies have indicated that chromosome 14q24.3 harbours a major locus for early-onset (onset age <65 years) Alzheimer's disease (AD3). Positional cloning efforts have identified a novel gene S182 or presenilin 1 as the AD3 gene. We have mapped S182 in the AD3 candidate region between D14S277 and D14S284 defined by genetic linkage studies in the two chromosome 14 linked, early-onset AD families AD/A and AD/B. We have shown that S182 is expressed in lymphoblasts and have determined the complete cDNA in both brain and lymphoblasts by RT-PCR sequencing. S182 is alternatively spliced in both brain and lymphoblasts within a putative phosphorylation site located 5' in the coding region. We identified two novel mutations, Ile143Thr and Gly384la located in, respectively, the second transmembrane domain and in the sixth hydrophilic loop of the putative transmembrane structure of S182. As families AD/A and AD/B have very similar AD phenotype our observation of two mutations in functionally different domains suggest that onset age and severity of AD may not be very helpful predictors of the location of putative S182 mutations.

Mutation analysis of the chromosome 14q24.3 dihydrolipoyl succinyltransferase (DLST) gene in patients with early-onset Alzheimer disease.

Linkage analysis studies have indicated that the chromosome band 14q24.3 harbours a major gene for familial early-onset Alzheimer's disease (AD). Recently we localized the chromosome 14 AD gene (AD3) in the 6.4 cM interval between the markers D14S289 and D14S61. We mapped the gene encoding dihydrolipoyl succinyltransferase (DLST), the E2k component of human alpha-ketoglutarate dehydrogenase complex (KGDHC), in the AD3 candidate region using yeast artificial chromosomes (YACs). The DLST gene is a candidate for the AD3 gene since deficiencies in KGDHC activity have been observed in brain tissue and fibroblasts of AD patients. The 15 exons and the promoter region of the DLST gene were analysed for mutations in chromosome 14 linked AD cases and in two series of unrelated early-onset AD cases (onset age < 55 years). Sequence variations in intronic sequences (introns 3, 5 and 10) or silent mutations in exonic sequences (exons 8 and 14) were identified. However, no AD related mutations were observed, suggesting that the DLST gene is not the chromosome 14 AD3 gene.

The apolipoprotein E epsilon 2 allele is associated with an increased risk of early-onset Alzheimer's disease and a reduced survival.

It was suggested that in contrast to the E4 allele, the E2 allele of the apolipoprotein E gene (APOE*2) has a protective effect for late-onset Alzheimer's disease and early-onset Alzheimer's disease (EOAD). We studied the role of the APOE*2 allele in the pathogenesis of EOAD in a Dutch population-based study of 175 probable EOAD patients with onset age at or before 65 years and 532 age-matched controls. In our population, there was no evidence for a protective effect of the APOE*2 allele on the risk of EOAD. However, our data show that among EOAD patients, survival for APOE*2 carriers was significantly reduced. When restricting the analysis to patients ascertained early after diagnosis at a stage of disease when mortality is low, our data suggest an increased risk of EOAD for subjects with APOE2E2, APOE2E3, APOE3E4, and APOE4E4 genotypes.

A population-based study of familial Alzheimer disease: linkage to chromosomes 14, 19, and 21.

Linkage of Alzheimer disease (AD) to DNA markers on chromosomes 14, 19, and 21 was studied in 10 families in which the disease was apparently inherited as an autosomal dominant trait. Families were derived from a Dutch population-based epidemiologic study of early-onset AD. Although in all probands the onset of AD was at or before age 65 years, the mean age at onset was after age 65 years in four families (referred to as "LOAD"). Among the six families with early-onset AD (referred to as "EOAD," i.e., mean age of onset of AD of relatives was at or before age 65 years), conclusive linkage to 14q24.3 was found in one family with a very early onset (around 47 years), while linkage to the same region was excluded in two other families. For the LOAD families, predominantly negative lod scores were obtained, and the overall lod score excluded linkage to chromosome 14. The results with markers on chromosome 19 and chromosome 21 were not conclusive for EOAD and LOAD. The findings of our study confirm genetic heterogeneity within familial EOAD.

Apolipoprotein E4 allele in a population-based study of early-onset Alzheimer's disease.

Several studies have reported an association of the apolipoprotein E allele epsilon 4 (APOE*4) to familial and sporadic late-onset Alzheimer's disease (LOAD). Here we report on the relationship between APOE*4 and early-onset Alzheimer's disease (EOAD) in a Dutch population-based study. The frequency of the APOE*4 allele was 2.3 times higher among EOAD cases compared to controls. Among patients, the allele frequency was 1.6 times higher in those with a positive family history than in those without. A significant increase in risk of EOAD was found for subjects homozygous for APOE*4 regardless of family history of dementia, but an increase in EOAD risk for APOE*4 heterozygotes could only be shown in subjects with a positive family history. Our study demonstrates a significant association between APOE*4 and EOAD which is modified by family history of dementia.

X-ray analysis of metal-substituted human carbonic anhydrase II derivatives.

Metal-substituted crystals of human carbonic anhydrase II belonging to space group P2(1) with cell dimensions a = 42.7, b = 41.7, c = 73.0 A and beta = 104.6 degrees were analyzed crystallographically. The resolution limit ranged from 1.82 to 1.92 A with high completeness (86.2-90.7%). Cobalt(II)-substituted carbonic anhydrase has a tetrahedral coordination around the metal both at pH 6 and pH 7.8, similar to the native zinc enzyme. In contrast, the catalytically inactive copper(II), nickel(II) and manganese(II) derivatives showed increased coordination number around the metal ion. Whereas the copper is best described as penta-coordinated, the nickel and manganese are best described as hexa-coordinated. The results are briefly compared with spectroscopic observations and our current view on carbonic anhydrase catalysis.

Structure of cobalt carbonic anhydrase complexed with bicarbonate.

The three-dimensional structure of a complex between catalytically active cobalt(II) substituted human carbonic anhydrase II and its substrate bicarbonate was determined by X-ray crystallography (1.9 A). One water molecule and two bicarbonate oxygen atoms are found at distances between 2.3 and 2.5 A from the cobalt ion in addition to the three histidyl ligands contributed by the peptide chain. The tetrahedral geometry around the metal ion in the native enzyme with a single water molecule 2.0 A from the metal is therefore lost. The geometry is difficult to classify but might best be described as distorted octahedral. The structure is suggested to represent a water-bicarbonate exchange state relevant also for native carbonic anhydrase, where the two unprotonized oxygen atoms of the substrate are bound in a carboxylate binding site and the hydroxyl group is free to move closer to the metal thereby replacing the metal-bound water molecule. A reaction mechanism based on crystallographically determined enzyme-ligand complexes is represented.

Unique sequence homology in the pericentromeric regions of the long arms of chromosomes 13 and 21.

We previously isolated two polymorphic chromosome 21q probes, pVC1.21c (D21S190) and pVC1.34a (D21S149), localized in 21qcen-21q21.2. In addition, pVC1.21c recognized a sequence in 21q22.1-q22.2 and both probes cross-hybridized with non-chromosome-21 sequences. In this study we refined the proximal 21q locations of probes pVC1.21c and pVC1.34a to 21q11.1 and demonstrated that they recognize sequences on chromosome 13 but not on chromosomes 14, 15, and 22. Furthermore, the polymorphisms associated with the two loci were assigned to pericentromeric 13q for pVC1.34a and distal 21q for pVC1.21c. Our results are indicative of a region of unique sequence homology in the pericentromeric region of the long arms of chromosomes 13 and 21.

Identification of chromosome 21 DNA polymorphisms for genetic studies in Alzheimer's disease and Down syndrome.

Linkage studies in families with presenile onset of Alzheimer's disease (AD) indicated the presence of a predisposing gene on the proximal long arm of chromosome 21. We mapped four new loci in the candidate AD region using somatic cell hybrids. For three of the four loci, several restriction fragment length polymorphisms were found; for one locus, a multiallelic (CA)n dinucleotide polymorphism was detected. Preliminary genetic mapping of the new polymorphic loci relative to the AD-linked loci was obtained in a reference pedigree. In addition, we used the (CA)n dinucleotide polymorphism to reconstruct the non-disjunction event in a Down syndrome (DS) patient whose mother died of familial AD.

Subregional localization of the chromosome 21 loci D21S24 and D21S26 using physical mapping techniques.

We were able to refine the chromosomal position of two existing marker loci, using an extended chromosome 21 somatic cell hybrid panel. The locus D21S26 mapped in the region 21q11.2-q21.1, and the locus D21S24 in 21q22.1-q22.2. Physical and genetic analysis indicated that D21S26 is tightly linked to D21S13 and D21S16, two markers previously linked to familial Alzheimer's disease.