Genetic investigation of chromosome 5q GABAA receptor subunit genes in schizophrenia.

We previously performed a genome-wide linkage scan in Portuguese schizophrenia families that identified a risk locus on chromosome 5q31-q35. This finding was supported by meta-analysis of 20 other schizophrenia genome-wide scans that identified 5q23.2-q34 as the second most compelling susceptibility locus in the genome. In the present report, we took a two-stage candidate gene association approach to investigate a group of gamma-aminobutyric acid (GABA) A receptor subunit genes (GABRA1, GABRA6, GABRB2, GABRG2, and GABRP) within our linkage peak. These genes are plausible candidates based on prior evidence for GABA system involvement in schizophrenia. In the first stage, associations were detected in a Portuguese patient sample with single nucleotide polymorphisms (SNPs) and haplotypes in GABRA1 (P=0.00062-0.048), GABRP (P=0.0024-0.042), and GABRA6 (P=0.0065-0.0088). The GABRA1 and GABRP findings were replicated in the second stage in an independent German family-based sample (P=0.0015-0.043). Supportive evidence for association was also obtained for a previously reported GABRB2 risk haplotype. Exploratory analyses of the effects of associated GABRA1 haplotypes on transcript levels found altered expression of GABRA6 and coexpressed genes of GABRA1 and GABRB2. Comparison of transcript levels in schizophrenia patients and unaffected siblings found lower patient expression of GABRA6 and coexpressed genes of GABRA1. Interestingly, the GABRA1 coexpressed genes include synaptic and vesicle-associated genes previously found altered in schizophrenia prefrontal cortex. Taken together, these results support the involvement of the chromosome 5q GABAA receptor gene cluster in schizophrenia, and suggest that schizophrenia-associated haplotypes may alter expression of GABA-related genes.

Theory of mind deficit in people with schizophrenia during remission.

BACKGROUND: The authors' goal was to investigate the presence or absence of theory of mind impairments among people with schizophrenia during remission. Recent research results interpret theory of mind deficits as state rather than trait characteristics, connecting these impairments mainly to the acute episode of psychosis. METHODS: Twenty patients with schizophrenia in remission and 20 matched control subjects were evaluated. Participants were presented with one first-order theory of mind task, one second-order theory of mind task, two metaphor and two irony tasks adapted from previous studies. RESULTS: The schizophrenic patients performed a statistically significant impairment in the irony task, as there were no significant differences in the cases of the other evaluated tasks. CONCLUSIONS: These preliminary results suggest that theory of mind impairments can be detected not only in the acute phase as found in previous research studies, but also in remission.

Schizophrenics show a failure in the decoding of violations of conversational implicatures.

OBJECTIVES: Recent approaches to the 'theory of mind' and pragmatics support that, if we did not have any idea about what other people know, we could hardly use language effectively. Successful communication (the pragmatic aspect of language) depends on inferring the beliefs and intentions of the partner in the conversation. Such successful communication is linguistically realized in part by cohesion and in part by abiding by the maxims derived from the cooperative principle. However, the violations of the Gricean implicatures are generally used in everyday language, mainly to point at a hidden, most commonly negative opinion on others. We hypothesize that schizophrenics have difficulties in the decoding of these violations, as the core deficit in this disorder is around social cognition, theory of mind and pragmatic language use. MATERIAL AND METHOD: We have examined 26 paranoid schizophrenic patients and 26 normal control subjects by using 4 'question and answer' vignettes, where the Gricean maxim of relevance was violated to express a hidden, negative opinion by one partner during the communicative act. The subjects were asked to judge these opinions and were evaluated by the investigators on a score from 0 to 2 points. In a pilot study, interrater reliability was judged to be satisfactory. The data were analysed statistically by parametric and non-parametric tests. RESULTS: Statistical analyses of our data have shown that schizophrenics made significantly more mistakes during the decoding of the violated maxim as compared with controls (p < 0.0001), reflecting on the difficulties during the correct exploration of the social context, i.e. recognition of the speaker's hidden opinion. CONCLUSION: We conclude that patients with schizophrenia fail to decode intentional violations of conversational implicatures. These results point at a dysfunctional pragmatic language use among schizophrenic patients.

Minor physical anomalies in schizophrenia and bipolar affective disorder.

OBJECTIVE: The prevalence of minor physical anomalies (MPAs) (prenatal errors of morphogenesis) was evaluated in patients with schizophrenia and bipolar affective disorder. METHOD: A new modification of the Waldrop-scale was used to detect the presence or absence of 57 MPAs in 30 patients with schizophrenia, 30 with bipolar disorder, and in 30 matched normal controls. RESULTS: Patients with schizophrenia compared to normal controls had significantly higher rates of three minor malformations (furrowed tongue, flat occiput, primitive shape of ears) and those of one phenogenetic variant (wide distance between toes 1 and 2), and they also had a significantly higher rate of one minor malformation (primitive shape of ears), as compared to patients with bipolar disorder. In patients with bipolar disorder, furrowed tongue was significantly more common than in controls. CONCLUSIONS: These results support an 'early' neuro-developmental model of schizophrenia.

Coexistence of delusions of pregnancy and infestation in a male.

The coexistent appearance of delusions of pregnancy and infestation is reported in a male patient with posttraumatic epilepsy. While published organic cases of delusions of pregnancy have involved patients with severe or mild mental retardation, our reported patient had a higher than average IQ. The interpretative role of these delusions in a probable perceptual symptomatology cannot be excluded, as both delusions can be based on sensations in the abdomen or on the skin.

Association analysis of NOTCH4 loci in schizophrenia using family and population-based controls.

A genetic association between NOTCH4 and schizophrenia has previously been proposed. Unsing all markers previously shown to be associated, we found no evidence for such in three independent family-based samples (n=519 parent-offspring trios), and a case-control sample derived from the same ethnic background as the original observation. These data strongly suggest that NOTCH4 is not a significant susceptibility allele for schizophrenia.

[Olanzapine and pregnancy]. / Olanzapin és terhesség.

The appearance of psychosis during pregnancy means a challenge for clinicians, either untreated psychiatric disorders or pharmacological treatment of pregnant psychotic females increase risk of complications. Controlled clinical trials can't be evaluated because of ethical considerations, so case reports have higher scientific values than in other clinical issues. The authors inform about a delivery of a young psychotic female, who was treated with olanzapine (atypical antipsychotic) after the 25th weeks of her pregnancy. A healthy newborn was born in the observed case, the Apgar score was 7 at the first minute and 9 at fifth minute.

Support for allelic association of a polymorphic site in the promoter region of the serotonin transporter gene with risk for alcohol dependence.

OBJECTIVE: An association between the 5-HTTLPR short variant polymorphism in the promoter region of the serotonin transporter gene and risk for alcohol dependence has been reported from case-control studies that are, however, prone to chance findings related to artifacts of population structure. The authors sought additional evidence for this association from a family-based study. METHOD: Ninety-two alcohol-dependent probands and their parents were tested for nonrandom transmission of alleles from heterozygous parents to affected probands. RESULTS: Preferential transmission of the short allele was found (65 of 102 transmissions from heterozygous parents). CONCLUSIONS: The results suggest allelic association between a variant in the promoter region of the serotonin transporter gene and the risk for alcohol dependence. However, it remains to be seen whether the functional properties of this variant are directly responsible for the increased risk to alcohol dependence.

A genome-wide autosomal screen for schizophrenia susceptibility loci in 71 families with affected siblings: support for loci on chromosome 10p and 6.

Evidence from epidemiological studies and segregation analysis suggests oligo- or polygenic inheritance in schizophrenia. Since model independent methods are thought to be most appropriate for linkage analysis in complex disorders, we performed a genome-wide autosomal screen in 71 families from Germany and Israel containing 86 independent affected sib-pairs with parental genotype information for statistical analysis strictly identity by descent. We genotyped 305 individuals with 463 markers at an average distance of approximately 10 cM genome-wide, and 1-2 cM in candidate regions (5q, 6p, q, 8p, 10p, 18p, 22q). The highest multipoint LOD scores (ASPEX) were obtained on 6p (D6S260, LOD = 2.0; D6S274, LOD = 2.2, MHC region, LOD = 2.15) and on 10p (D10S1714, LOD = 2.1), followed by 5q (D5S2066, LOD = 1.36), 6q (D6S271, LOD = 1.12; D6S1613, LOD = 1.11), 1q (D1S2675, LOD = 1.04), and 18p (broad disease model: D18S1116, LOD = 1.0). One hundred and thirty-three additional family members were available for some of the families (extended families) and were genotyped for these regions. GENEHUNTER produced a maximum NPL of 3.3 (P = 0.001) for the MHC region and NPL of 3.13 (P = 0.0015) for the region on 10p. There is support for these regions by independent groups. In genome-wide TDT analysis (sTDT, implemented in ASPEX), no marker passed the significance level of 0.0001 given by multiple testing, but nominal significance values for D10S211 (P = 0.03) and for GOLF (P = 0.0032) support further the linkage results on 10p and 18p. Our survey of 22 chromosomes identified candidate regions which should be useful to screen for schizophrenia susceptibility genes.

Transmission/disequilibrium tests using multiple tightly linked markers.

Transmission/disequilibrium tests have attracted much attention in genetic studies of complex traits because (a) their power to detect genes having small to moderate effects may be greater than that of other linkage methods and (b) they are robust against population stratification. Highly polymorphic markers have become available throughout the human genome, and many such markers can be studied within short physical distances. Studies using multiple tightly linked markers are more informative than those using single markers. However, such information has not been fully utilized by existing statistical methods, resulting in possibly substantial loss of information in the identification of genes underlying complex traits. In this article, we propose novel statistical methods to analyze multiple tightly linked markers. Simulation studies comparing our methods versus existing methods suggest that our methods are more powerful. Finally, we apply the proposed methods to study genetic linkage between the dopamine D2 receptor locus and alcoholism.

Antipsychotics and breast-feeding: a review of the literature.

Many women with mental illnesses would like to breast feed their infants. In light of the limited but rapidly growing data, it seems that in some cases the possible physiological and psychological benefits may outweigh putative risks. All antipsychotics are secreted into breast milk but the concentrations and effects vary. There is a subgroup of mothers with mental illnesses who want to breast feed their infants and who are receiving a single established antipsychotic drug (principally, haloperidol or chlorpromazine) at the lowest possible clinically effective dose. As a tentative conclusion, this group could experience benefits from being able to nurse which would outweigh the risk of exposing their babies to very small amounts of antipsychotic drugs. However, larger study groups with longer follow-up periods would be required to confirm this tentative conclusion. Those mothers who require 2 or more antipsychotic drugs simultaneously and those taking one drug, but at the upper end of the recommended dose range, should not be advised to breast feed. Safety considerations suggest that women taking atypical antipsychotics would be advised not to breast feed because of the limited experience with these agents. When mothers taking antipsychotic drugs do nurse, it is desirable to monitor drug concentrations in breast milk and in the infants themselves. Close monitoring of the infant is essential.

[A case of datura stramonium poisoning--general problems of differential diagnosis]. / Csattanómaszlag-mérgezés esete--a differenciáldiagnózis gyakorlati kérdései.

In past year drug abuse becomes more and more general in Hungary. In addition to consume traditional drugs, other substances are used frequently too. One of them is the Datura stramonium, which contains alkaloids (mostly atropine), and can result in hallucinations. Therefore Datura stramonium is seemingly becoming popular as a hallucinogenic drug. The consumption of any part of the plant causes atropine intoxication, thus anticholinergic delirium. Differential diagnosis of Datura intoxication can be difficult in the everyday medical practise. In our paper the symptomatology, diagnosis, differential diagnosis, and therapy of Datura intoxication are discussed and we report one of our cases.

["Folie a deux hallucinatoire"--a new case of induced hallucinatory psychosis. A new entity?]. / "Folie a deux hallucinatoire"--indukált hallucinózis újabb esete. Uj entitás?

The authors in their case report show a case of induced hallucinatory psychosis induced in a wife of a patient with alcoholic hallucinosis. They deal with the nosological position of "folie a deux hallucinatoire" (induced hallucinatory psychosis) and integrate the consequences of the case to the general psychopathological theory of hallucinations.

DAT1 gene polymorphism in alcoholism: a family-based association study.

BACKGROUND: The present study tests the hypothesis that the 9-repeat allele of the dopamine transporter gene (DAT1; SLC6A3) is more frequent in alcohol-dependent probands--and in particular those with severe withdrawal symptoms (seizures and/or delirium)--compared to nonalcoholics. METHODS: To avoid stratification effects, the family-based association approach of Falk and Rubinstein was used in our sample of 87 alcohol-dependent probands and their biological parents. RESULTS: By applying a family-based association approach, we were not able to detect significant association between allele 9 at DAT1 (SLC6A3) and alcoholism as well as between patients with or without severe withdrawal symptoms. CONCLUSIONS: Based on our data, the impact of the 9-repeat allele of the dopamine transporter gene in alcoholism and the severity of alcohol withdrawal symptoms is putatively not substantial.

Silver staining of selected mitoses by physical development.

A silver staining method using light-insensitive physical developer for electron microscopic study of selected mitoses is described. The G-banded mitoses are stained with silver by a physical development process that preserves the original G-banding pattern. Transferring the light microscopically selected mitoses to grids provides an examination by optional high resolution in an electron microscope. The physical developer makes the staining standardizable and reproducible, and the intensity of the staining can be controlled by varying the time of development.

Support for a chromosome 18p locus conferring susceptibility to functional psychoses in families with schizophrenia, by association and linkage analysis.

The action of antipsychotic drugs on dopamine receptors suggests that dopaminergic signal transmission may play a role in the development of schizophrenia. We tested eight candidate genes (coding for dopamine receptors, the dopamine transporter, and G-proteins) in 59 families from Germany and Israel, for association. A P value of .00055 (.0044 when corrected for the no. of markers tested) was obtained for the intronic CA-repeat marker G-olfalpha on chromosome 18p. The value decreased to .000088 (.0007) when nine sibs with recurrent unipolar depressive disorder were included. Linkage analysis using SSLP markers densely spaced around G-olfalpha yielded a maximum two-point LOD score of 3.1 for a marker 0.5 cM distal to G-olfalpha. Multipoint analysis under the assumption of heterogeneity supported this linkage-whether the affected pheotype was defined narrowly or broadly-as did nonparametric linkage (NPL). In 12 families with exclusively maternal transmission of the disease, the NPL value also supported linkage to this marker. In order to test for association/linkage disequilibrium in the presence of linkage, the sample was restricted to independent offspring. When this sample was combined with 65 additional simplex families (each of them comprising one schizophrenic offspring and his or her parents), the 124-bp allele of G-olfalpha was transmitted 47 times and was not transmitted 21 times (P=.009). These results suggest the existence, on chromosome 18p, of a potential susceptibility locus for functional psychoses.

Further evidence for a susceptibility locus on chromosome 10p14-p11 in 72 families with schizophrenia by nonparametric linkage analysis.

Recent reports on potential linkage by Faraone and the NIMH Genetics Initiative-Millennium Schizophrenia Consortium [1997: Am J Med Genet 74:557], and by Straub et al. [1997: Am J Med Genet 74:558], prompted us to study chromosome 10 in a sample of 72 families containing 2 or more affected sibs with schizophrenia for additional evidence of linkage. We obtained highest allele sharing for the two markers D10S582 (61.5% allele sharing, chi2 = 7.6, P = 0.0058) and D10S1423 (59% allele sharing, chi2 = 4.76, P = 0.029). D10S1423 is one of the markers with the highest lod scores in the study of Faraone and the NIMH Genetics Initiative-Millennium Schizophrenia Consortium [1997: Am J Med Genet 74:557]. GENEHUNTER analysis revealed a nonparametric lod score (NPL) of 3.2 (P = 0.0007) for the marker D10S1714, which lies in the same region. Multipoint affected sib-pair lod score analysis (identity by descent) calculated by ASPEX revealed a lod score of 1.72 for all possible sib-pair combinations (107) and of 2.13, when only independent sib-pairs (87) were counted. Our study provides further evidence for a potential susceptibility locus for schizophrenia on chromosome 10p.

Antipsychotic use in pregnancy. What are the best treatment options?

Both the rapid emergence of new antipsychotic medications and the increasing fertility rate among women with psychotic disorders have contributed to the growing clinical importance of the treatment of pregnant women who have psychotic illnesses. The treatment of this patient population must always take into consideration the effect of that treatment on the fetus. With regard to the high risk of decompensation during pregnancy and postpartum, continuous antipsychotic medication is needed using the minimum effective dose. The use of high-potency agents appears to be preferable for first-line management, as there are few data regarding the use of atypical agents such as clozapine in pregnancy. Guidelines for treating pregnant women with psychoses vary little from those for nonpregnant patients. Clinicians must always carefully weigh up the risks and benefits for each patient on an individual basis.

Informative morphogenetic variants in patients with schizophrenia and alcohol-dependent patients: beyond the Waldrop Scale.

OBJECTIVE: The authors evaluated the presence or absence of informative morphogenetic variants in patients with schizophrenia compared with alcohol-dependent patients. METHODS: Taking into consideration the criticisms of the Waldrop Scale, which was widely used until recently to define the presence of informative morphogenetic variants, the authors evaluated the presence or absence of 56 informative morphogenetic variants in 50 consecutively admitted patients with schizophrenia and 50 consecutively admitted alcohol-dependent patients. They made a distinction between minor malformations (those developing during organogenesis) and phenogenetic variants (those developing after organogenesis). A kappa index above 75% was considered reliable. RESULTS: Thirty-four of the 56 informative morphogenetic variants met the authors' reliability criterion. Patients with schizophrenia had significantly higher rates of three minor malformations (furrowed tongue, multiple buccal frenula, and hemangioma) and two phenogenetic variants (protruding auricle and large tongue). CONCLUSIONS: The results suggest that using finer distinction in the evaluation of informative morphogenetic variants in schizophrenia may open new perspectives in the research of the neurodevelopmental background of schizophrenia.