Neurocognitive functioning in patients with first-episode schizophrenia: results of a prospective 15-year follow-up study.

To evaluate the course of neuropsychological impairment, patients with first-episode schizophrenia and healthy controls were assessed with a comprehensive test battery at the time of index treatment and after a 5- and 15-year follow-up period. Summary scores for verbal intelligence (VBI), spatial organization, verbal fluency, verbal learning, semantic memory, visual memory, delay/retention rate, short-term memory, visual-motor processing and attention (VSM) and abstraction/flexibility were constructed. Our results show that neurocognitive functioning is impaired already at the onset of schizophrenia and remains stable over the 15-year follow-up period with an improvement in VBI. With regard to the presence of a deficit syndrome, it became apparent that the group with a deficit syndrome showed a deterioration of neurocognitive functions during the follow-up period, most pronounced in VSM. On the other hand, the group without a deficit syndrome showed an improvement in neurocognitive functions at the 15-year follow-up, which exceeded the learning effects of healthy control subjects. Neurocognitive performance at index assessment strongly predicted the performance at the 15-year follow-up. Most likely due to the small sample size, there were only weak associations between treatment with different types of neuroleptics and neurocognitive performance.

What can patients do to facilitate shared decision making? A qualitative study of patients with depression or schizophrenia and psychiatrists.

PURPOSE: Patient involvement in decision making is endorsed by patients and professionals. While research has recently been conducted on how professionals can promote shared decision making (SDM), little is known about how patients can also facilitate SDM. METHODS: Seven focus groups were conducted: 3 with psychiatrists and 4 with patients with schizophrenia or depression. The focus groups were transcribed and independently coded line by line by 2 researchers. Data were analyzed using content analysis. RESULTS: Seven themes related to patient attitudes and behaviors were identified: honesty and openness with one's psychiatrist and oneself, trust in one's psychiatrist and patience with the treatment, respect and politeness, informing the psychiatrist and giving feedback, engagement/active participation during the consultation, gathering information/preparing for the consultation and implementing decisions. Barriers (e.g., avolition, lack of decisional capacity, powerlessness during involuntary treatment) and facilitators of active patient behavior were also identified. CONCLUSIONS: There are various ways in which patients can facilitate SDM/play a more active role in decision making, with patients emphasizing being open and honest and psychiatrists emphasizing being active in the consultation. Interventions to increase active patient behavior may enhance SDM in mental health care.

Clinical courses of schizophrenia.

Schizophrenia is a complex disorder, characterized by molecular, neuroendocrine, and behavioral alterations as well as gene-environment interactions. This article summarizes key facts on the diagnosis, long-term course and neurocognitive deficits of schizophrenia. Due to the heterogeneity of schizophrenia with regard to symptomatology, illness manifestations, course and outcome, the focus of attention has shifted from diagnostic categories to endophenotypes which are hoped to characterize distinct subtypes of schizophrenia more appropriately than the diagnostic classification systems. The systems approach aims to assess the complexity and multiple dynamics of biological systems to explain endophenotypes of schizophrenia and their associations with susceptibility genes. Data presented in this paper support the view that looking for associations between neurocognitive endophenotypes and susceptibility genes might be a promising approach for future research to elucidate the heterogeneity of schizophrenic spectrum disorders.

Systems biology and addiction.

The onset of addiction is marked with drug induced positive experiences that keep being repeated. During that time, adaptation occurs and addiction is stabilized. Interruption of those processes induces polysymptomatic withdrawal syndromes. Abstinence is accompanied by risks of relapse. These features of addiction suggest adaptive brain dynamics with common pathways in complex neuronal networks. Addiction research has used animal models, where some of those phenomena could be reproduced, to find correlates of addictive behavior. The major thrust of those approaches has been on the involvement of genes and proteins. Recently, an enormous amount of data has been obtained by high throughput technologies in these fields. Therefore, (Computational) "Systems Biology" had to be implemented as a new approach in molecular biology and biochemistry. Conceptually, Systems Biology can be understood as a field of theoretical biology that tries to identify patterns in complex data sets and that reconstructs the cell and cellular networks as complex dynamic, self-organizing systems. This approach is embedded in systems science as an interdisciplinary effort to understand complex dynamical systems and belongs to the field of theoretical neuroscience (Computational Neuroscience). Systems biology, in a similar way as computational neuroscience is based on applied mathematics, computer-based computation and experimental simulation. In terms of addiction research, building up "computational molecular systems biology of the (addicted) neuron" could provide a better molecular biological understanding of addiction on the cellular and network level. Some key issues are addressed in this article.

Genomewide linkage scan of schizophrenia in a large multicenter pedigree sample using single nucleotide polymorphisms.

A genomewide linkage scan was carried out in eight clinical samples of informative schizophrenia families. After all quality control checks, the analysis of 707 European-ancestry families included 1615 affected and 1602 unaffected genotyped individuals, and the analysis of all 807 families included 1900 affected and 1839 unaffected individuals. Multipoint linkage analysis with correction for marker-marker linkage disequilibrium was carried out with 5861 single nucleotide polymorphisms (SNPs; Illumina version 4.0 linkage map). Suggestive evidence for linkage (European families) was observed on chromosomes 8p21, 8q24.1, 9q34 and 12q24.1 in nonparametric and/or parametric analyses. In a logistic regression allele-sharing analysis of linkage allowing for intersite heterogeneity, genomewide significant evidence for linkage was observed on chromosome 10p12. Significant heterogeneity was also observed on chromosome 22q11.1. Evidence for linkage across family sets and analyses was most consistent on chromosome 8p21, with a one-LOD support interval that does not include the candidate gene NRG1, suggesting that one or more other susceptibility loci might exist in the region. In this era of genomewide association and deep resequencing studies, consensus linkage regions deserve continued attention, given that linkage signals can be produced by many types of genomic variation, including any combination of multiple common or rare SNPs or copy number variants in a region.

Systems biology and psychiatry - modeling molecular and cellular networks of mental disorders.

Biological psychiatry has more and more directed it's focus on the involvement of genes and molecules in mental health and disease. On these levels, new approaches in other medical fields are noticed that are collectively dubbed "Systems Biology". Conceptually, this new paradigm tries to view molecular interactions in cellular networks as dynamic, self-organizing events that eventually result in an ordered maintenance of the whole system. A great deal of applied mathematics is required in systems biology to set up and carry out computer modeling and simulation. In terms of psychiatric research, developing "systems biology of the neuron" could become a pivotal achievement for a better understanding of mental illness on the molecular level. A brief outline of imminent tasks and links between systems biology and biological psychiatry is presented.

Evaluation of association of SNPs in the TNF alpha gene region with schizophrenia.

The association of the tumor necrosis factor alpha (TNFalpha) -G308A promoter polymorphism with schizophrenia has complemented clinical findings of increased levels of the TNFalpha cytokine in schizophrenic patients, with some support for a functional consequence of the variant. Our previous studies of genetic causes in schizophrenia supported findings of linkage to the major histocompatibility complex (MHC) region where the TNFalpha gene is located as well as association with the -G308A promoter polymorphism. While the common G-allele shows association in our sample, association with the A-allele has been reported by other groups. This suggests linkage disequilibrium (LD) rather than direct involvement in the disorder. In order to define LD of DNA variants with the disorder in this area, we analyzed 36 SNPs in a 165-kb region around this polymorphism. We detected nominally significant associations (P < 0.05) of three markers (including the -G308A promoter polymorphism) and multiple haplotypes with schizophrenia in our sample of 204 families (79 sib-pairs and 125 trios). The association is largely restricted to a 30 kb high LD region/block and should assist in the identification of a schizophrenia susceptibility gene within the block or elsewhere in the MHC.

Evidence for association of DNA sequence variants in the phosphatidylinositol-4-phosphate 5-kinase IIalpha gene (PIP5K2A) with schizophrenia.

Linkage studies in schizophrenia have identified a candidate region on chromosome 10p14-11 as reported for several independent samples. We investigated association of DNA sequence variants in a plausible candidate gene located in this region, the gene for phosphatidylinositol-4-phosphate 5-kinase IIalpha (PIP5K2A), in a sample of 65 sib-pair families for which linkage had been reported. Evidence for association was obtained for 15 polymorphisms spanning 73.6 kb in the genomic region of the gene between intron 4 and the 3' untranslated region, a region with high degree of linkage disequilibrium. Single nucleotide polymorphism (SNP) rs10828317 located in exon 7 and causing a non-synonymous amino-acid exchange (asparagine/serine) produced a P-value of 0.001 (experiment-wide significance level 0.00275) for over-transmission of the major allele coding for serine, analysed by transmission disequilibrium test using FAMHAP. Association of this SNP with schizophrenia has been also described in a sample of 273 Dutch schizophrenic patients and 580 controls (P=0.0004). PIP5K2A is involved in the biosynthesis of phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2), one of the key metabolic crossroads in phosphoinositide signalling. PI(4,5)P2 plays a role in membrane transduction of neurotransmitter signals as well as in intracellular signalling, pathways that may be impaired in schizophrenia.

Towards systemic theories in biological psychiatry.

Although still rather controversial, empirical data on the neurobiology of schizophrenia have reached a degree of complexity that makes it hard to obtain a coherent picture of the malfunctions of the brain in schizophrenia. Theoretical neuropsychiatry should therefore use the tools of theoretical sciences like cybernetics, informatics, computational neuroscience or systems science. The methodology of systems science permits the modeling of complex dynamic nonlinear systems. Such procedures might help us to understand brain functions and the disorders and actions of psychiatric drugs better.

Genome-wide scan for genes involved in bipolar affective disorder in 70 European families ascertained through a bipolar type I early-onset proband: supportive evidence for linkage at 3p14.

Preliminary studies suggested that age at onset (AAO) may help to define homogeneous bipolar affective disorder (BPAD) subtypes. This candidate symptom approach might be useful to identify vulnerability genes. Thus, the probability of detecting major disease-causing genes might be increased by focusing on families with early-onset BPAD type I probands. This study was conducted as part of the European Collaborative Study of Early Onset BPAD (France, Germany, Ireland, Scotland, Switzerland, England, Slovenia). We performed a genome-wide search with 384 microsatellite markers using non-parametric linkage analysis in 87 sib-pairs ascertained through an early-onset BPAD type I proband (AAO of 21 years or below). Non-parametric multipoint analysis suggested eight regions of linkage with P-values<0.01 (2p21, 2q14.3, 3p14, 5q33, 7q36, 10q23, 16q23 and 20p12). The 3p14 region showed the most significant linkage (genome-wide P-value estimated over 10 000 simulated replicates of 0.015 [0.01-0.02]). After genome-wide search analysis, we performed additional linkage analyses with increased marker density using markers in four regions suggestive for linkage and having an information contents lower than 75% (3p14, 10q23, 16q23 and 20p12). For these regions, the information content improved by about 10%. In chromosome 3, the non-parametric linkage score increased from 3.51 to 3.83. This study is the first to use early-onset bipolar type I probands in an attempt to increase sample homogeneity. These preliminary findings require confirmation in independent panels of families.

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.

Multicenter linkage study of schizophrenia loci on chromosome 22q.

The hypothesis of the existence of one or more schizophrenia susceptibility loci on chromosome 22q is supported by reports of genetic linkage and association, meta-analyses of linkage, and the observation of elevated risk for psychosis in people with velocardiofacial syndrome, caused by 22q11 microdeletions. We tested this hypothesis by evaluating 10 microsatellite markers spanning 22q in a multicenter sample of 779 pedigrees. We also incorporated age at onset and sex into the analysis as covariates. No significant evidence for linkage to schizophrenia or for linkage associated with earlier age at onset, gender, or heterogeneity across sites was observed. We interpret these findings to mean that the population-wide effects of putative 22q schizophrenia susceptibility loci are too weak to detect with linkage analysis even in large samples.

[High dose L-thyroxine in therapy refractory depression. Case analysis and catamnesis as quality control]. / L-Thyroxin-Hochdosierung bei therapieresistenter Depression. Fallauswertung und Katamnese als Qualitätskontrolle.

In a depression unit in a state hospital, 28 patients who had failed in six antidepressant strategies were treated with L-thyroxine at an average dose of 350 micro g/die. Outcomes were moderate in 39.3% and very good in 21.5%, corresponding to 21-item HAMD scores of < or =16 and < or =8 and clinical judgement. Of all patients, 39.3% had to stop treatment due to nonresponse or side effects. Follow-up of all responders to treatment was conducted 45.2 weeks after discharge. Those 28.6% patients who had stopped treatment had significantly more readmissions, i.e., 62.5%, vs none in those who continued, whereas subjective clinical ratings did not differ between the two groups. In contrast to the literature not finding serious side effects in 70 mainly bipolar patients, we found cardial arrhythmia in 10.7% of inpatients and 7.1% of follow-up patients that was serious enough to discontinue treatment. In conclusion, systematic investigation of high-dose L-thyroxine treatment in treatment-resistant depression seems promising and necessary.

[Diagnostic value of three-dimensional reconstruction in CT of traumatic spinal fractures]. / Wertigkeit der dreidimensionalen Rekonstruktion in der CT-Diagnostik traumatischer Wirbelsäulenfrakturen.

PURPOSE: Evaluation of the diagnostic value of three-dimensional CT-reconstruction in the pre-operative evaluation of traumatic fractures of the spine, compared with axial slices and two-dimensional reconstruction. MATERIALS AND METHODS: The CT image data of 65 patients with 85 different acute traumatic spine fractures (C 2 through L 5) were collected in a period of 42 months. Retrospectively performed 2D- and 3D-reconstructions were analyzed independently by three CT-experienced readers using the Magerl classification and the readings compared with intraoperative findings or the final diagnoses. RESULTS: The fractures were classified according to the AO-classification as 56 compression, 16 distraction and 13 rotation fractures. Axial slices alone incorrectly classified 2 (1.2 %) of 168 (56 fractures x 3 readers) type A fractures. The CT classification was incorrect in 17 (35.4 %) of 48 (16 fractures x 3 readers) type B fractures and in 31 (79.5 %) of 39 (13 fractures x 3 readers) type C fractures. The 2D-reconstruction increased the percentage of incorrect diagnoses to 13 (7.7 %) type A, to 26 (54.2 %) type B and to 27 (69.2 %) type C fractures. The 3D-mode incorrectly classified 2 of 168 type A fractures (1.2 %), 6 of 48 type B fractures (12.5 %), and 1 of 39 type C fractures (2.6 %). The axial mode was superior to the 2D-reconstructions in type A and type B fractures, but inferior in type C fractures. The percentage of correctly classified type B fractures was significantly higher (p < 0.05) with 3D-reconstruction than with the 2D-mode. In type C fractures, this percentage was significantly higher (p < 0.001) with the 3D-mode than with axial slices or 2D-reconstruction. The interactive monitor analysis of the 3D-reconstructions with additional virtual cutting by the reader improved the analysis, especially the evaluation of the spinal canal. CONCLUSION: The 3D-reconstruction in traumatic spine fractures significantly improves the diagnostic outcome, especially the visualization and classification of rotation fractures. Its disadvantages are a slight increase in artifacts and impaired visualization of small details. Interactive monitor analysis and post-processing of the 3D-mode proved to be advantageous.

Psychopathology in dual-diagnosis and nonaddicted schizophrenics: are there differences?

Analysis of 447 schizophrenic inpatients found a lifetime prevalence for substance use of 42.9% (3-month prevalence 29%). While the overall differences were small between schizophrenics using (dual diagnosis) and those not using substances, dual-diagnosis patients in general reported more positive symptoms, especially more intense hallucinations. These differences were observed in patients with current (3-month) substance use on admission but not on discharge, possibly as a result of substance use. The most marked differences were in previous suicide attempts and delinquency, which were more prevalent in dual-diagnosis schizophrenics. These findings indicate that patients with dual diagnosis are more disturbed than other schizophrenics. We discuss the implications for the self-medication hypothesis for substance use in schizophrenia and future research in this area are discussed.

A genome screen for genes predisposing to bipolar affective disorder detects a new susceptibility locus on 8q.

Bipolar affective disorder (BPAD), also known as manic depressive illness, is a severe psychiatric disorder characterized by episodes of mania and depression. It has a lifetime prevalence of approximately 1% in all human populations. In order to identify chromosomal regions containing genes that play a role in determining susceptibility to this psychiatric condition, we have conducted a complete genome screen with 382 markers (average marker spacing of 9.3 cM) in a sample of 75 BPAD families which were recruited through an explicit ascertainment scheme. Pedigrees were of German, Israeli and Italian origin, respectively. Parametric and non-parametric linkage analysis was performed. The highest two-point LOD score was obtained on 8q24 (D8S514; LOD score = 3.62), in a region that has not attracted much attention in previous linkage studies of BPAD. The second best finding was seen on 10q25-q26 (D10S217; LOD score = 2.86) and has been reported in independent studies of BPAD. Other regions showing 'suggestive' evidence for linkage localized to 1p33-p36, 2q21-q33, 3p14, 3q26-q27, 6q21-q22, 8p21, 13q11 and 14q12-q13. In addition, we aimed at detecting possible susceptibility loci underlying genomic imprinting by analyzing the autosomal genotype data with the recently developed extension of the GENEHUNTER program, GENEHUNTER-IMPRINTING. Putative paternally imprinted loci were identified in chromosomal regions 2p24-p21 and 2q31-q32. Maternally imprinted susceptibility genes may be located on 14q32 and 16q21-q23.

Association between the 5' UTR variant C178T of the serotonin receptor gene HTR3A and bipolar affective disorder.

Serotonin receptor type 3 is a ligand-gated ion channel implicated in behavioural disorders. Our objective was to identify nucleotide variants in a specific portion of the 5' region of the serotonin receptor gene (HTR3A) containing upstream open reading frames (uORFs) and to investigate their effect on bipolar disease. Mutations in uORFs have been recently shown to cause disease by changing expression on the translational level. We identified one polymorphism, C195T, and one missense mutation, C178T (Pro16Ser) within an upstream open reading frame. No significant association was found between the C195T polymorphism and bipolar affective disorder. A significant association was, however, found between the variant C178T in 156 patients with bipolar disorder compared to 156 healthy controls (P = 0.00016). To investigate the relevance of this variant on gene expression, luciferase reporter constructs containing the C178T (Pro16Ser) allele were established and compared to the C178T plus C195T and wild-type alleles. Reporter constructs containing the C178T (Pro16Ser) allele drove 245% and 138% expression compared to the wild-type allele. These findings show that the C178T(Pro16Ser) variant in HTR3A may represent a functional variant and affect the susceptibility to bipolar disorder.

[Established and atypical neuroleptics. What the family physician should know]. / Etablierte und atypische Neuroleptika. Was der Hausarzt wissen sollte.

Some 30-50% of schizophrenic patients fail to respond at all, or only inadequately, to the classical neuroleptics. The side effects profile is broad--in particular adverse reactions affecting the extrapyramidal motor system may be induced. In recent years, numerous, so-called atypical neuroleptic agents have been approved. These substances are characterized by improved efficacy and fewer side effects. The downside, however, is that they are considerably more expensive than the established neuroleptics. A further disadvantage is the fact that no depot preparations are as yet available. Finally, some of these substances lead to a marked increase in weight.

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.

A possible susceptibility locus for bipolar affective disorder in chromosomal region 10q25--q26.

In an attempt to identify susceptibility loci for bipolar affective disorder, we are currently conducting a systematic genome screen with highly polymorphic microsatellite markers at an average marker spacing of 10 cM in a series of 75 families, comprising 66 families from Germany, eight families from Israel, and one family from Italy. The families were ascertained through index cases with bipolar affective disorder. The distribution of diagnoses is as follows: 126 individuals with bipolar I disorder, 40 with bipolar II disorder, 14 with schizoaffective disorder of the bipolar type, 40 individuals with recurrent unipolar depression, 51 with a minor psychiatric diagnosis, and two individuals with a diagnosis of schizophrenia. One hundred and seventy-one individuals are unaffected. Here, we present results from chromosome 10. Linkage analyses using a total of 33 microsatellite markers with parametric and non-parametric methods provided evidence for linkage at chromosomal region 10q25--q26. The highest two-point LOD score (2.86, theta = 0.05) was obtained for D10S217 using a dominant genetic model and a broad definition of affection status. The GENEHUNTER program localized the putative susceptibility locus within a ca 15-cM interval between markers D10S1483 and D10S217 with a maximum NPL(all) score of 3.12 (P = 0.0013). Positive linkage findings that have been reported by two independent studies further support the hypothesis of a susceptibility gene for bipolar affective disorder on 10q25-q26.