Comprehension of metaphors in patients with schizophrenia-spectrum disorders.

BACKGROUND: Metaphors, mainly proverbs and idiomatic expressions of ordinary life are commonly used as a model for concretism. Previous studies have shown impaired metaphor comprehension in patients with schizophrenia-spectrum disorders compared to either psychiatric or non-psychiatric control subject. The aim of this study was to detect possible quantitative differences in figurative processing between patients with schizophrenia-spectrum disorders and healthy controls. METHODS: In order to analyse possible dissociations of different aspects of figurative speech, a range of metaphor tasks was used to distinguish between recognition of familiar metaphors, paraphrasing the meaning of the latter and generating novel metaphors: we used a standard proverb test for conventional metaphors consisting of a multiple-choice and a paraphrasing task, and the Metaphoric Triads Test for the assessment of novel metaphors. We included 40 patients with schizophrenia-spectrum disorders and 43 healthy control subjects. RESULTS: Our results showed that patients had impaired figurative speech processing regarding novel and conventional metaphors. Associations with cognitive functions were detected. Performance on the paraphrasing task was associated with the severity of negative symptoms. CONCLUSION: We conclude that patients with schizophrenia-spectrum disorders do exhibit impairments in the recognition and paraphrasing of conventional and the generation of novel metaphors and that some cognitive domains as well the extent of negative symptoms might be associated with these deficits.

Interaction between serotonin 5-HT2A receptor gene and dopamine transporter (DAT1) gene polymorphisms influences personality trait of persistence in Austrian Caucasians.

We examined 89 normal volunteers using Cloninger's Temperament and Character Inventory (TCI). Genotyping the 102T/C polymorphism of the serotonin 5HT2A receptor gene and the ser9gly polymorphism in exon 1 of the dopamine D3 receptor (DRD3) gene was performed using PCR-RFLP, whereas the dopamine transporter (DAT1) gene variable number of tandem repeats (VNTR) polymorphism was investigated using PCR amplification followed by electrophoresis in an 8% acrylamide gel with a set of size markers. We found a nominally significant association between gender and harm avoidance (P=0.017; women showing higher scores). There was no association of either DAT1, DRD3 or 5HT2A alleles or genotypes with any dimension of the TCI applying Kruskal-Wallis rank-sum tests. Comparing homozygote and heterozygote DAT1 genotypes, we found higher novelty seeking scores in homozygotes (P=0.054). We further found a nominally significant interaction between DAT1 and 5HT2A homo-/heterozygous gene variants (P=0.0071; DAT1 and 5HT2A genotypes P value of 0.05), performing multivariate analysis of variance (MANOVA). Examining the temperamental TCI subscales, this interaction was associated with persistence (genotypes: P=0.004; homo-/heterozygous gene variants: P=0.0004). We conclude that an interaction between DAT1 and 5HT2A genes might influence the temperamental personality trait persistence.

Sequence analysis of the complete SLITRK1 gene in Austrian patients with Tourette's disorder.

Mutations in the gene SLITRK1 (Slit and Trk-like 1) have been reported in patients with Tourette's disorder (TD). We sequenced the entire SLITRK1 gene including the coding region the 5' and 3' untranslated region in 92 Austrian patients with TD. No nucleotide changes within the protein-coding region were identified. One patient was found to carry a variant within the 3' untranslated region (3383g>a), which was absent in 192 control individuals and which segregated in two additional family members with tic symptoms. In conclusion, our results provide no evidence for SLITRK1 playing a major role in TD.

Additional support for linkage of schizophrenia and bipolar disorder to chromosome 3q29.

After publishing a genome scan and follow-up fine mapping, suggesting schizophrenia and bipolar disorder linkage to chromosome 3q29, we now genotyped 11 additional SNPs (single nucleotide polymorphisms), in order to narrow down a potential candidate region. Linkage was performed using the GENEHUNTER program version 2.1r3. A NPL score Z(all) of 3.891 (p=0.000156) was observed with SNP rs225. In short, we found significant linkage scores most telomeric on chromosome 3q29, spanning 3.46 Mbp (7 SNPs).

Molecular and genomic studies of IMMP2L and mutation screening in autism and Tourette syndrome.

We recently reported the disruption of the inner mitochondrial membrane peptidase 2-like (IMMP2L) gene by a chromosomal breakpoint in a patient with Gilles de la Tourette syndrome (GTS). In the present study we sought to identify genetic variation in IMMP2L, which, through alteration of protein function or level of expression might contribute to the manifestation of GTS. We screened 39 GTS patients, and, due to the localization of IMMP2L in the critical region for the autistic disorder (AD) locus on chromosome 7q (AUTS1), 95 multiplex AD families; however, no coding mutations were found in either GTS or AD patients. In addition, no parental-specific expression of IMMP2L was detected in somatic cell hybrids containing human chromosome 7 and human cell lines carrying a maternal uniparental disomy for chromosome 7 (mUPD7). Despite the fact that no deleterious mutations in IMMPL2 (other than the inverted duplication identified previously) were identified in either GTS or AD, this gene cannot be excluded as a possible rare cause of either disorder.

Homozygosity of the interleukin-10 receptor 1 G330R allele is associated with schizophrenia.

Infections of unknown origin and an altered immune response have been hypothesized to play a role in the pathogenesis of schizophrenia. We have previously identified two single nucleotide polymorphisms (SNPs) of the IL-10 receptor 1 (IL-10R1) causing a substitution of glycine 330 to arginine (G330R) and of serine 138 to glycine (S138G). A possible association between these IL-10R1 variants and schizophrenia has been investigated in the present study. DNA of 101 unrelated Austrian patients with a DSM-III-R (Diagnostic and Statistical Manual of Mental Disorders) consensus diagnosis of schizophrenia (n = 70) or schizoaffective disorder (n = 31) and DNA of 121 German schizophrenic patients (DSM-III-R) was analyzed for the presence of S138G and G330R by allele-specific multiplex PCRs. Data from patients were compared with 250 unrelated, psychiatric healthy controls. No difference in allele frequency was detected between patients and controls (G330R: 34.0% vs. 30.0%, P = 0.208; S138G: 19.7% vs. 16.6%, P = 0.235; by Fisher's exact test). However, there was a significant difference in genotype distribution (wt/wt, wt/mut, mut/mut) for G330R between patients (46.8%, 38.3%, 14.9%) and controls (47.6%, 44.8%, 7.6%; Fisher's test P = 0.032). No such difference was seen for S138G. Our results suggest that homozygosity of the IL-10R1 G330R allele is associated with schizophrenia and may contribute to the expression of disease phenotype in susceptible individuals.

Combined analysis of 635 patients confirms an age-related association of the serotonin 2A receptor gene with tardive dyskinesia and specificity for the non-orofacial subtype.

Tardive dyskinesia (TD) is an important limiting factor in the use of typical antipsychotic drugs. Genetic variability in the serotonin 2A (5-HT(2A)) receptor may influence risk for TD but the results of prior studies are not confirmatory. The objective of this study was to determine association of T102C and His452Tyr polymorphisms in the 5-HT(2A) receptor gene (HTR(2A)) with TD in a large, multicentre patient sample. The design employed case-control analysis controlling for possible confounders using pooled, original data from published and available unpublished samples and employing logistic regression, analysis of variance and meta-analysis. The study sample consisted of 635 patients with schizophrenia or schizoaffective disorder (256 with TD and 379 without TD) drawn from five research centres, divided into six groups based on population origin. The main outcome measure was association of a categorical diagnosis of TD based on the Research Diagnostic Criteria for TD with HTR(2A) T102C and His452Tyr genotypes and haplotypes. The findings indicate significant association of TD with HTR(2A) T102C genotype (p=0.002) over and above the effect of population group, also when controlling for age and gender (p=0.0008), but not with His452Tyr genotype. The T102C genotype was significantly associated with TD in older (>median age 47 yr, p=0.002) but not younger patients and in patients with non-orofacial (limb-truncal) (p=0.001) but not orofacial TD. By meta-analysis the Mantel-Haenszel (M-H) pooled odds ratio (OR) across all the available data was 1.64. A T102C-His452Tyr haplotype was significantly associated with TD (p=0.0008). These findings confirm that genetic variability in HTR(2A) contributes a small but significant degree of risk for the expression of TD, particularly in older patients and specifically for the non-orofacial (limb-truncal) type. Together with other genetic variants associated with TD the findings could be used to assess risk in patients who are candidates for treatment with typical antipsychotic medications.

Possible linkage of schizophrenia and bipolar affective disorder to chromosome 3q29; a follow-up.

The present linkage study is a follow-up within the chromosome 3q29 region in schizophrenia and bipolar affective disorder families, based on our recently published genome scan, resulting in evidence for linkage of both disorders to this region (marker D3S1265: NPL [non parametric lod] score Z(all)=3.74, P=0.003). Using the same family sample (five pedigrees with schizophrenic index patients and three pedigrees with index bipolar disorder patients N=86; 50 of them were available for genotyping), genotyping of eight additional markers close to D3S1265 was done. Five of those new markers (three centromeric and two telomeric of D3S1265) spanning 4.14 cM (centiMorgan) could be used for statistical analyses ("new markers"). Moreover, marker D3S1265, genotyped within the published genome scan, was used for additional calculations. Linkage analysis was performed using the GENEHUNTER program version 2.1r3. Within newly genotyped markers the highest NPL score Z(all) observed was 1.93296 with the telomeric SNP (single nucleotide polymorphism) rs1835669, corresponding to P=0.032166. Statistical analysis including D3S1265, located in between the newly genotyped markers, resulted in a peak NPL score Z(all)=4.00179 with marker D3S1265, that is P=0.000128. Doing subset analyses of the bipolar disorder and schizophrenia families separately with new markers and D3S1265, linkage signals arose substantially from bipolar disorder families, with contribution from schizophrenia families, too. The results of our follow-up study support our previous linkage finding of schizophrenia and bipolar affective disorder to chromosome 3q29.

[In search of susceptibility genes for schizophrenia]. / Auf der Suche nach Vulnerabilitätsgenen der Schizophrenie.

After the recent discovery and replication of several schizophrenia candidate regions on multiple chromosomes, susceptibility genes for schizophrenia could be identified for the first time. Each of these discoveries resulted from association studies within chromosomal regions first identified by linkage analyses. Within the last two years, the susceptibility genes Neuregulin1, Dysbindin, D-amino-acid-oxidase (DAAO) and G72 were discovered, which, in the variant forms, reduce glutamatergic activity in brain. Therefore, they are related to the so-called "Glutamate-hypothesis", which postulates a hypofunction of the glutamatergic system. Adults with VCFS (velo-cardio-facial-syndrome), where a deletion on chromosome 22q11 can be found, show a very high incidence of schizophrenia. In addition, 2% of patients with schizophrenia exhibit this 22q11-deletion. Within the VCFS-deleted region on chromosome 22q11, the genes coding for proline dehydrogenase (PRODH) and catechol-O-methyltransferase (COMT) were also found to be significantly associated with schizophrenia. Proline is a pre-stage of glutamate, and in addition, it seems to be a neuromodulator of glutamatergic transmission in the brain. COMT is one of the two enzymes degrading catecholamines such as dopamine. Therefore, it plays a large role in the cortical dopamine metabolism. Furthermore, an association of schizophrenia with the gene RGS4 (regulator-of-G-protein-signaling-4), a modulator of the function of multiple G-protein-linked neurotransmitter receptors, was identified. Gene-expression-analyses of postmortem cerebral cortex (prefrontal) indicate that the transcription of RGS4 is diminished within schizophrenics. In accordance with the fact that schizophrenia is a disease with a multifactorial etiology, it should be emphasized that the described biological risk factors can increase susceptibility, but that none of them can cause the disease alone.

Anxiety as a predictor of relapse in detoxified alcohol-dependent patients.

AIMS: To evaluate the impact of mood, affect, and personality on predicting relapse in detoxified alcohol-dependent patients to uncontrolled drinking during a 1-year treatment study. METHODS: A total of 521 patients with a DSM-III-R diagnosis of alcohol dependence, excluding those with major depressive disorder, took part in a European multicentre study (11 centres in the United Kingdom, Irish Republic, Switzerland, and Austria). Depressive symptoms were assessed using the Hamilton Depression Scale, whereas symptoms of anxiety were measured using the 'STAI-X2' of the self-rating scale State-Trait Anxiety Inventory and personality traits were measured by the Tridimensional Personality Questionnaire. RESULTS: High anxiety as a stable trait, and personality traits such as high novelty seeking and low harm avoidance covering exploratory excitability, impulsiveness, extravagance, disorderliness and uninhibited optimism, predicted relapse. CONCLUSIONS: These measures could have a direct clinical application for predicting relapse to uncontrolled drinking in male and female detoxified alcohol-dependent patients. The findings indicate the importance of additional therapeutic treatment.

Maternal bonding behaviour in schizophrenia and schizoaffective disorder, considering premorbid personality traits.

OBJECTIVE: Bonding between mother and child is described as a complex two-way process ensuring the needs of the child for nurture and protection. As such, it is dependent on the contribution of mother and child [1-3] whereby characteristics of personality of the child may have consequences on maternal bonding behaviour. In the current study the perception of maternal behaviour, premorbid personality traits and relationships between maternal behaviour and personality traits were investigated in schizophrenic and schizoaffective patients and their same-sex, healthy siblings. METHODS: We recruited 36 schizophrenic and schizoaffective patients and their same-sex healthy siblings. Information about maternal bonding behaviour was assessed by the Parental Bonding Instrument, information about premorbid personality traits was obtained from their mothers using the "Giessen-Test". RESULTS: Compared to their siblings, patients showed less social resonance, more permeability, less social competence and a more depressed and anxious mood. Furthermore, patients described their mothers to be less caring and to be more overprotective than their siblings described them. But there were strong associations between maternal bonding behaviour and premorbid personality traits. These findings were supported by missing significant differences in maternal care behaviour between patients and siblings when using premorbid characteristics as covariates. Significant high maternal overprotection perceived by patients with schizophrenia and schizoaffective disorders still remained after correcting for the influence of premorbid personality traits. CONCLUSION: The results suggest that premorbid personality traits should be considered not only in analyses of maternal care behaviour in schizophrenic and schizoaffective patients but also when studying other psychiatric patient groups.

Pharmacogenetics of tardive dyskinesia: combined analysis of 780 patients supports association with dopamine D3 receptor gene Ser9Gly polymorphism.

Variability among individuals in their therapeutic response to psychotropic drugs and in susceptibility to adverse effects is considerable. Pharmacogenetics addresses the contribution of genetic factors to this variability. An important focus of interest in pharmacogenetics has been on candidate genes that play a role in susceptibility to the antipsychotic drug-induced adverse effect, tardive dyskinesia (TD). Four published studies have reported an association between a serine (ser) to glycine (gly) polymorphism in exon 1 of the dopamine D3 receptor gene (DRD3) and TD; three failed to replicate this finding and one found an insignificant trend. We examined the association in a pooled sample of 780 patients (317 with TD and 463 without TD) drawn from 6 research centers, who were divided into 8 groups based on their population origin. The analysis employed stepwise logistic regression so as to allow confounding effects of group, age, and gender to be taken into account. TD was significantly associated with DRD3 gly allele carrier status (x(2)=4.46, df 1, p =.04) and with DRD3 genotype (x(2)=6.62, df 2, p =.04) over and above the effect of group. Similar positive effects were observed when controlling for age and gender (x(2)=5.02, df 1, p =.02 for gly allele carrier status; x(2) = 7.51, df 2, p =.002 for genotype). Examining abnormal involuntary movement scores as a continuous variable, we found that patients homozygous for the gly allele had significantly higher scores than ser-gly heterozygotes (p =.006) or ser-ser homozygotes (p <.0001). We also performed a meta-analysis that included, besides the groups in the combined analysis, three other published studies on DRD3 and TD. The Mantel-Haenszel pooled odds ratio for DRD3 gly allele carrier status increasing susceptibility to TD was 1.33 (95% CI 1.04-1.70, p =.02); the cumulative pooled estimate showed an odds ratio of 1.52 (95% CI 1.08-1.68, p <.0001). These findings support a small but significant contribution of the DRD3 ser9gly polymorphism to TD susceptibility that is demonstrable over and above population effects and the effect of age and gender on the phenotype.

Genome scan for susceptibility loci for schizophrenia and bipolar disorder.

BACKGROUND: Despite the widely accepted view that schizophrenia and bipolar disorder represent independent illnesses and modes of inheritance, some data in the literature suggest that the diseases may share some genetic susceptibility. The objective of our analyses was to search for vulnerability loci for the two disorders. METHODS: A genomewide map of 388 microsatellite DNA markers was genotyped in five schizophrenia and three bipolar disorder Austrian families. Linkage analyses was used to compute the usual parametric logarithm of the likelihood of linkage (LOD) scores and nonparametric linkage analysis (NPL scores Z(all)) was used to assess the pattern of allele sharing at each marker locus relative to the presence of the disease (GENEHUNTER). Affected status was defined as severe affective disorder or schizophrenia. RESULTS: Across the genome, p values associated with NPL scores resulted in evidence (i.e., p <.0007) for linkage at marker D3S1265 on chromosome 3q (NPL score Z (all) = 3.74, p =.0003). Two other markers (on 3q and 6q) showed p values of <.01. CONCLUSIONS: We detected a potential susceptibility locus for bipolar disorder and schizophrenia on chromosome 3q, which has not been reported previously. The possibility of a false positive result has to be taken into account. Our data suggest shared loci for schizophrenia and bipolar affective disorders and are consistent with the continuum model of psychosis.