Description of the Genetic Analysis Workshop 10 bipolar disorder linkage data sets.
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Bipolar Disorder↗
Biomedical subjects
M Albus
Publications and source records attributed to M Albus.
D2-dopamine-receptor occupancy during treatment with haloperidol decanoate.
We investigated in an open, explanatory study a total of 24 patients meeting DSM-III-R criteria for schizophrenia. Eighteen patients were treated for at least 4 weeks with a fixed dose of orally administered haloperidol for at least 4 weeks (mean daily dosage ranging from 0.07 to 0.35 mg/kg b.w.), and 6 patients received haloperidol decanoate with a fixed dose for at least 4 months (dosage range 50-150 mg/4 weeks; calculated mean daily dosage ranging from 0.02 to 0.09 mg/kg b.w.). One week after injection of haloperidol decanoate, the single photon emission computed tomography examination was performed. Our data suggest that D2-dopamine-receptor occupancy of 50 mg/4 weeks haloperidol decanoate 1 week after injection corresponds to an oral dose of 4.5 mg/day haloperidol.
Adult↗
Physiological, biochemical and subjective parameters in anxiety patients with panic disorder during stress exposure as compared with healthy controls.
Physiological (heart rate, blood pressure, electrodermal activity), biochemical (epinephrine, norepinephrine, cortisol) and subjective parameters (self-rating score) of 33 patients with panic disorder (diagnoses according to DSM-III-R) before, during and after stress exposure were compared with those of healthy controls. As stressors a video containing frightening scenes (FS), mental arithmetic (MA), a video documenting a patient suffering from a panic attack (PA) and an improvised speech (IS) were applied. We found significantly higher baseline levels of electrodermal activity (EDA) and norepinephrine (NE) secretion and a subsequent further increase during stress exposure in panic disorder patients as compared with normal controls. The most potent stressors during the trial proved to be mental arithmetics and improvised speech, which was evident in both groups. The situation panic attack video appeared to be a "panic disorder patient-specific" stressor; here we noticed the most pronounced reactions in the patient group. Panic disorder patients had significantly higher self-rating scores of the parameters panicky feelings, anxiety and nervousness at the beginning and throughout the investigation. We conclude that panic disorder patients have a higher degree of activation compared with normal controls, which is evident regarding levels of electrodermal activity and norepinephrine secretion. Furthermore, the panic attack video appears to be a panic disorder patient-specific stressor.
Adult↗
Evidence suggestive of a locus on chromosome 5q31 contributing to susceptibility for schizophrenia in German and Israeli families by multipoint affected sib-pair linkage analysis.
Suggestive evidence for a potential susceptibility locus for schizophrenia at 5q31 was obtained in two family samples. Sample I consisted of 14 families with schizophrenia and revealed for the marker IL9 a lod score of 1.8 by two point lod score analysis. Sample II comprised 44 families including four from sample I and was ascertained in order to employ affected sib-pair analysis by identity by descent. A lod score of 1.8 around the marker D5S399 was obtained by multipoint analysis. The lod score remained positive, but decreased to 1.27 when the four families from sample I were excluded in order to use sample II as a statistically independent replication sample. We propose a susceptibility locus for schizophrenia with probably minor contribution in the pedigrees under investigation.
Chromosomes, Human, Pair 5↗
Predictors and outcome in panic disorder: a 2-year prospective follow-up study.
53 patients presenting at an outpatient unit for anxiety disorders were included in the present prospective 2-year follow-up study. Sociodemographic, illness history, index rating, and 2-year follow-up data were evaluated. A multiple stepwise regression analysis was carried out in order to find predictors of the 2-year outcome. Results indicate that panic patients without episode at follow-up show less symptoms and a better psychosocial functioning than patients with episode at follow-up. Comorbid generalized anxiety disorder, duration of illness, and phobic avoidance behavior were found to be the best predictors of outcome. Conclusively, the present study confirms the most important predictors in patients with panic disorder.
Adult↗
Predictors of outcome in panic disorder: a 5-year prospective follow-up study.
A prospective 5-year follow-up study in patients with panic disorder was carried out in order to determine predictors of outcome. 50 patients presenting at an outpatient clinic for anxiety disorders were enrolled initially in a controlled treatment study using either imipramine or doxepin in addition to supportive psychotherapy and were then followed under naturalistic treatment conditions. By means of multiple stepwise regression analyses comorbidity with current depression, severity of illness and agoraphobic avoidance turned out to be the strongest predictors. These data confirm the findings of shorter-term prospective follow-up studies and of retrospective studies. In contrast to several reports, illness-related social impairment at baseline was not found to affect outcome.
Adolescent↗
Systematic screening for mutations in the 5'-regulatory region of the human dopamine D1 receptor (DRD1) gene in patients with schizophrenia and bipolar affective disorder.
A possible dysregulation of dopaminergic neurotransmission has been implicated in a variety of neuropsychiatric diseases. In the present study we systematically searched for the presence of mutations in the 5'-flanking region of the dopamine D1 receptor (DRD1) gene. This region has previously been shown to contain a functional promoter [Minowa et al., 1992: Proc Natl Acad Sci 89:3045-3049; Minowa et al., 1993: J Biol Chem 268:23544-23551]. We investigated 119 unrelated individuals (including 36 schizophrenic patients, 38 bipolar affective patients, and 45 healthy controls) using single-strand conformation analysis (SSCA). Eleven overlapping PCR fragments covered 2,189 bp of DNA sequence. We identified six single base substitutions: -2218T/C, -2102C/A, -2030T/C, -1992G/A, -1251G/C, and -800T/C. None of the mutations was found to be located in regions which have important influence on the level of transcriptional activity. Allele frequencies were similar in patients and controls, indicating that genetic variation in the 5'-regulatory region of the DRD1 gene is unlikely to play a frequent, major role in the genetic predisposition to either schizophrenia or bipolar affective disorder.
Alleles↗
Systematic screening for mutations in the human serotonin 1F receptor gene in patients with bipolar affective disorder and schizophrenia.
Using single strand conformational analysis we screened the complete coding sequence of the serotonin 1F (5-HT1F) receptor gene for the presence of DNA sequence variation in a sample of 137 unrelated individuals including 45 schizophrenic patients, 46 bipolar patients, as well as 46 healthy controls. We detected only three rare sequence variants which are characterized by single base pair substitutions, namely a silent T-->A transversion in the third position of codon 261 (encoding isoleucine), a silent C-->T transition in the third position of codon 176 (encoding histidine), and an C-->T transition in position -78 upstream from the start codon. The lack of significant mutations in patients suffering from schizophrenia and bipolar affective disorder indicates that the 5-HT1F receptor is not commonly involved in the etiology of these diseases.
Base Sequence↗
Human adenosine A2a receptor (A2aAR) gene: systematic mutation screening in patients with schizophrenia.
Several lines of evidence suggest an involvement of adenosine A2a receptor (A2aAR) mediated adenosinergic neuromodulation in the etiopathogenesis of schizophrenia. We therefore performed a systematic mutation scan of the complete coding region of the human A2aAR gene in a sample of 42 schizophrenic patients. We detected one rare naturally occurring receptor variant (Gly-340-Ser) and two silent mutations (405C/T and 1083C/T). To our knowledge the Gly-340-Ser substitution is the first naturally occurring molecular variant of the A2aAR identified. Determining the frequency of the three variants in 42 unrelated healthy controls, we observed a significant trend towards an overrepresentation of the 1083T variant in patients when compared to controls (p = 0.041). This trend was followed up in a large independent replication sample. However, we were not able to confirm the original trend in the second sample (p = 0.367). The Ser-340 variant was found in a single schizophrenic individual. Investigation of the patient's family revealed independent segregation between the Ser-340 variant and psychiatric illness. Our data suggest that genetically determined structural variation of the A2aAR does not play a major role in the development of schizophrenia.
Alleles↗
Neuropsychological impairment in first-episode and chronic schizophrenic patients.
Patients with first-episode (FE) schizophrenia (n = 40), with chronic schizophrenia (n = 40) and healthy controls (n = 40) matched for age, gender, education and parental socioeconomic status were administered a battery of standardized neuropsychological (NP) tests. Both patient groups showed generalized impairment relative to controls and the most pronounced deficits in visual-motor processing and attention (VSM). Compared with FE patients, chronic schizophrenics performed worse in VSM and abstraction/flexibility. Our findings suggest that NP deficits are fundamental manifestations of the illness, and that mainly frontally based dysfunctions are more prominent in chronic, kraepelinian patients.
Acute Disease↗
Systematic screening for mutations in the human serotonin-2A (5-HT2A) receptor gene: identification of two naturally occurring receptor variants and association analysis in schizophrenia.
A statistically significant association between a silent mutation (102T/C) in the serotonin-2A (5-HT2A) receptor gene and schizophrenia has recently been reported in a sample of Japanese patients and healthy controls. This finding suggests that genetic predisposition to schizophrenia may be affected by a functional 5-HT2A receptor variant that is in linkage disequilibrium with 102T/C. In the present study, we have sought to identify genetic variation in the 5-HT2A receptor gene by screening genomic DNA samples from 91 unrelated subjects comprising 45 patients with schizophrenia and 46 healthy controls by using single-strand conformation analysis. We have identified four nucleotide sequence variants. Two sequence changes would result in protein alterations: a substitution of threonine by asparagine at position 25 (Thr25Asn), and a substitution of histidine by tyrosine at position 452 (His452Tyr). In order to test for a possible contribution to the development of schizophrenia, we have determined allele frequencies in extended samples of unrelated patients and healthy controls. The two amino acid substitutions are found with similar frequencies in patients and controls, indicating that the presence of these variants is not causally related to the development of schizophrenia. However, the reported association of the non-coding polymorphism 102T/C with the disease has also been detected in our sample (P=0.041, odds ratio=1.28, 95% confidence interval 1.012-1.623).
Alleles↗
Dopamine D3 receptor Gly9/Ser9 polymorphism and schizophrenia: no increased frequency of homozygosity in German familial cases.
Disturbances in the dopaminergic transmission have been implicated in the etiology of schizophrenia. Recently, an association of schizophrenia with increased homozygosity of a Gly9/Ser9 polymorphism in the dopamine D3 receptor gene (DRD3) has been reported (Crocq et al., 1992; Mant et al., 1994). This finding reflected a departure from the Hardy-Weinberg equilibrium in the genotype distribution observed in schizophrenic patients. The effect was found to be at its strongest in patients with a high familial loading. In the present study, we tried to replicate this finding in a sample of 146 German patients with a DSM-III-R diagnosis of schizophrenia. All patients had a positive family history of major psychiatric disorder including 70 patients with a family history of schizophrenia. Given our sample size, we have a power of 99.8% to detect 2. deviation from the Hardy-Weinberg equilibrium of the reported magnitude. However, we found no evidence of an excess of homozygosity in our schizophrenic patients. This seems to indicate that homozygosity for the Gly9/Ser9 polymorphism at the DRD3 locus is unlikely to confer susceptibility to schizophrenia in the German population. This held true whether the psychiatric diagnoses in the affected relatives of the patient samples was established by the family history or family interview method.
Adult↗
Genetic relationship between dopamine transporter gene and schizophrenia: linkage and association.
This study explores the genetic relationship between schizophrenia and the dopamine transporter gene (DAT) by a variety of methods. In a sample of 48 families--each family containing at least one nuclear family with a pair of affected siblings--we performed linkage analysis using the maximum likelihood (LOD score) method as well as sibpair analysis (identity by descent). In addition, we investigated a sample of 108 nuclear families--index case affected with schizophrenia/chronic schizoaffective disorder--for association using the haplotype relative risk method. Linkage between schizophrenia and DAT using two- and three-point linkage analysis was excluded with all disease models employed. No evidence for association between haplotypes of the VNTR-probe of the DAT and schizophrenia has been detected. Thus, a contribution of the DAT gene to the genetic diathesis of schizophrenia is unlikely in the families studied.
Adult↗
Contrasts in neuropsychological test profile between patients with first-episode schizophrenia and first-episode affective disorders.
Patients with first-episode (FE) schizophrenia (n = 27), unipolar depression (n = 10) and bipolar disorder (n = 17) and age- and gender-matched healthy control subjects (n = 27) were administered a battery of neuropsychological (NP) tests. FE schizophrenics performed significantly less well than patients with affective disorders in the area of visual motor processing and attention. Affective disorder patients without psychotic features did not perform significantly differently to controls. However, affective disorder patients with psychotic features performed as poorly as schizophrenics, with the most pronounced impairment in the area of visual motor processing and attention. Our data tentatively suggest the existence of a dichotomy in neuropsychological impairment, with psychotic patients showing similar neuropsychological deficits, while non-psychotic affective patients perform comparably to controls.
Adult↗
Schizophrenia, schizotypal and delusional disorders (F2). Results from the ICD-10 field trial of the Diagnostic Criteria for Research in German-speaking countries.
The results of the ICD-10 field trial of the Diagnostic Criteria for Research in German-speaking countries concerning section F2, "Schizophrenia, schizotypal and delusional disorders', are presented. From a total of 39 cases (written case reports and video tapes) 5 met the criteria for schizophrenia (F20) with 201 ratings. The majority of clinicians rated the ease of diagnosis, confidence of diagnosis, and goodness of fit positive. The reliability of the 2-character diagnoses was excellent (F2; kappa = 0.88), as was the case for the category schizophrenia (F20; kappa = 0.89) and was higher than in the comparable study concerning the Clinical Diagnostic Guidelines.
Adolescent↗
Disorders of adult personality and behaviour (F6). Results from the ICD-10 field trial of the Diagnostic Criteria for Research in German-speaking countries.
Results of the ICD-10 Diagnostic Criteria for Research (DCR) field trial in German-speaking countries revealed a high level of interrater reliability (kappa = 0.79) for disorders of adult personality and behaviour (section F6) with marked differences between specific diagnoses: borderline personality = 0.76, transsexualism = 0.98, factitious disorder = 0.33. Compared with the results of the field trial concerning the Clinical Guidelines for section F6 of ICD-10, the application of the more precise and restrictive DRC led to an improvement of general kappa values of 0.15.
Factitious Disorders↗
The human serotonin 7 (5-HT7) receptor gene: genomic organization and systematic mutation screening in schizophrenia and bipolar affective disorder.
In the present study, we evaluated the possible contribution of genetic variation of the serotonin 5-HT7 receptor to the development of schizophrenia and bipolar affective disorder. Cloning and characterization of exon-flanking intronic sequences enabled us to investigate the whole coding region and the exon-intron boundaries of the human 5-HT7 receptor gene. Using single-strand conformational analysis, we screened for presence of DNA sequence variation in a sample of 137 unrelated individuals including 45 schizophrenic and 46 bipolar affective patients, as well as 46 healthy controls. We detected two rare naturally occurring receptor variants (Pro-279-Leu, Thr-92-Lys) and a silent nucleotide substitution (A-->G) at position +1233. The occurrence of the Pro-279-Leu and Thr-92-Lys substitutions was studied in an extended sample of patients (n = 462) and controls (n = 335). The Leu-279 variant was found in similar frequency in all groups, indicating that presence of this variant is not causally related to the development of schizophrenia or bipolar affective disorder. The Lys-92 variant was found in a single individual who suffered from bipolar affective disorder. Investigation of the patient's family revealed independent segregation between the Lys-92 variant and psychiatric illness. Our data suggests that genetic variation of the 5-HT7 receptor does not play a major role in the development of bipolar affective disorder and schizophrenia.
Bipolar Disorder↗
Searching for susceptibility genes in schizophrenia by genetic linkage analysis.
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Chromosomes, Human, Pair 18↗