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.

Evaluation of a susceptibility gene for schizophrenia on chromosome 6p by multipoint affected sib-pair linkage analysis.

The influence of genetic factors in schizophrenia has been convincingly demonstrated by family, twin and adoption studies, but the mode of transmission remains uncertain. The reported pattern of recurrence risks suggests a set of interacting loci. Based on prior evidence for linkage on chromosome 6p (K. Kendler, pers. comm.), we have scanned the short arm of chromosome 6 in 54 families for loci predisposing to schizophrenia, using 25 microsatellite markers spanning 60 centiMorgans (cM). Allele sharing identity by descent was examined in affected sib-pairs from these families, followed by multipoint sib-pair linkage analysis. Positive lod scores were obtained over a wide region (D6S470 to D6S271), with a maximum lod score of 2.2 occurring near D6S274, located in 6p22. However, we obtained a lod score of -2 at D6S296, the locus found by others to provide the greatest linkage evidence. At D6S274, we report a positive lod score as do Straub et al. (individually non-significant). A combined total lod of 3.6-4.0 suggests the possibility of a susceptibility locus in this region. However, methodological differences between our studies makes a firm conclusion difficult.

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.

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.

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 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.

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.

Serotonin receptor gene HTR3A variants in schizophrenic and bipolar affective patients.

Serotonin receptor genes have always been considered excellent candidate genes in the aetiology of neurogenetic diseases. In this study, we assessed sequence variations of the HTR3A gene. For this purpose, we established exon-specific primers and analysed DNA samples from 165 unrelated individuals including 70 schizophrenic patients, 48 patients with bipolar affective disorder and 47 healthy control persons using polymerase chain reaction/single-strand conformational polymorphism analysis. We discovered six sequence variants, five of which represent polymorphisms. These polymorphisms could not be associated with schizophrenia and bipolar affective disorder (P = 0.055-1). We also detected a missense mutation in exon 9 in a schizophrenic patient at a conserved position (Pro391Arg). To determine the incidence of this substitution an extended set of 358 schizophrenic patients and 155 control individuals was investigated. The Pro391Arg mutation was not detected in these schizophrenic patients and controls screened. However, a second missense mutation (Arg344His) was detected in one schizophrenic patient, but not in any of the controls. These results suggest that the observed mutations in HTR3A are rare and therefore do not play a major role in the aetiology of the disorder. Further studies are needed to support the hypothesis that HTR3A may contribute to the schizophrenia in these patients.

Tardive dyskinesia: relation to computer-tomographic, endocrine, and psychopathological variables.

Severity of tardive dyskinesia (TD) and psychopathology of 36 chronic schizophrenic patients under long-term treatment with neuroleptics (NL) was rated during NL therapy and again 12 days after NL withdrawal. Both times serum levels of prolactin, norepinephrine, beta-endorphin, and cortisol were determined. In 27 of these patients ventricular-brain ratio, width of third ventricle, maximal width of anterior horns, distance between choroid plexus, and width of four largest sulci were also measured. Fifteen patients had no signs of TD; 14 had moderate, and 7 severe TD. TD was not related to age, age at onset of illness, duration of illness, dosage and type of neuroleptics, number of ECTs, or any endocrine variable. Psychopathology was barely related to TD, but after NL withdrawal, patients with TD tended to show more deterioration, particularly with regard to thought disorder and activation. With regard to computer-tomographic (CT) variables, patients without TD showed significantly less sulcal enlargement than those with TD. These results indicate that individual predisposition, which may have led to the development of TD, also seems to involve a higher risk of relapse after NL withdrawal.

Outcome of panic disorder with or without concomitant depression: A 2-year prospective follow-up study.

In a prospective 2-year follow-up study, 32 patients with panic disorder alone and 20 with panic disorder and concomitant depression were investigated. After controlled treatment with either imipramine or doxepin, patients received naturalistic treatment with antidepressants, benzodiazepines, and supportive psychotherapy. They were evaluated for anxiety, depression, and social disability at least every 3 months during the follow-up period. The data showed fluctuation of symptoms in both groups and a less favorable outcome for the patients with comorbid conditions. However, the overall outcome was better than that reported in other studies and indicates that panic disorder is quite responsive to appropriate treatment.

Controllable and uncontrollable stress in humans: alterations in mood and neuroendocrine and psychophysiological function.

The authors exposed 10 healthy human volunteers to the stress of loud (100 dB) noise under controllable and uncontrollable conditions on two separate days. Subjects reported higher self-ratings of helplessness, lack of control, tension, stress, unhappiness, anxiety, and depression; had greater hypothalamic-pituitary-adrenal axis function as measured by elevations in plasma adrenocorticotropic hormone; and had higher levels of sympathetic nervous system and electrodermal activity after the uncontrollable stress condition than after exposure to controllable stress. Thus, lack of control over even a mildly aversive stimulus can produce alterations in mood as well as neuroendocrine and autonomic nervous system changes in healthy subjects.

Systematic screening for mutations in the promoter and the coding region of the 5-HT1A gene.

In the present study we sought to identify genetic variation in the 5-HT1A receptor gene which through alteration of protein function or level of expression might contribute to the genetic predisposition to neuropsychiatric diseases. Genomic DNA samples from 159 unrelated subjects (including 45 schizophrenic, 46 bipolar affective, and 43 patients with Tourette's syndrome, as well as 25 healthy controls) were investigated by single-strand conformation analysis. Overlapping PCR (polymerase chain reaction) fragments covered the whole coding sequence as well as the 5' untranslated region of the 5-HT1A gene. The region upstream to the coding sequence we investigated contains a functional promoter. We found two rare nucleotide sequence variants. Both mutations are located in the coding region of the gene: a coding mutation (A-->G) in nucleotide position 82 which leads to an amino acid exchange (Ile-->Val) in position 28 of the receptor protein and a silent mutation (C-->T) in nucleotide position 549. The occurrence of the Ile-28-Val substitution was studied in an extended sample of patients (n = 352) and controls (n = 210) but was found in similar frequencies in all groups. Thus, this mutation is unlikely to play a significant role in the genetic predisposition to the diseases investigated. In conclusion, our study does not provide evidence that the 5-HT1A gene plays either a major or a minor role in the genetic predisposition to schizophrenia, bipolar affective disorder, or Tourette's syndrome.

Potential linkage for schizophrenia on chromosome 22q12-q13: a replication study.

In an attempt to replicate a potential linkage on chromosome 22q12-q13.1 reported by Pulver et al. [1994: Am J Med Genet 54:36-43], we have analyzed 4 microsatellite markers which span this chromosomal region, including the IL2RB locus, for linkage with schizophrenia in 30 families from Israel and Germany. Linkage analysis by pairwise lod score analysis as well as by multipoint analysis did not provide evidence for a single major gene locus. However, a lod score of Zmax = 0.612 was obtained for a dominant model of inheritance with the marker D22S304 at recombination fraction 0.2 by pairwise analysis. In addition, using a nonparametric method, sib pair analysis, a P value of 0.068 corresponding to a lod score of 0.48 was obtained for this marker. This finding, together with those of Pulver et al. [1994: Am J Med Genet 54:36-43] and Coon et al. [1994: Am J Med Genet 54:72-79], is suggestive of a genetic factor in this region, predisposing for schizophrenia in a subset of families. Further studies using nonparametric methods should be conducted in order to clarify this point.

Association of dopamine D3-receptor gene variants with neuroleptic induced akathisia in schizophrenic patients: a generalization of Steen's study on DRD3 and tardive dyskinesia.

Neuroleptic induced akathisia is a common and distressful extrapyramidal side effect of antipsychotic treatment. A significant proportion of the variability of its development has been left unexplained and has to be attributed to individual susceptibility. Since hereditary factors have been discussed in the etiology of acute akathisia (AA), part of the individual susceptibility might be of genetic origin. Moreover, AA is regarded as a forerunner of tardive dyskinesia, a drug-induced chronic movement disorder, which may be associated with homozygosity for the Ser9Gly variant of the DRD3 gene. Considering expression studies, which demonstrated functional variants of DRD3 polymorphisms, we investigated whether homozygosity for the Ser9Gly variant of the DRD3 gene is associated with AA. Homozygosity for the Ser9Gly variant of the DRD3 gene was connected to an 88% incidence of AA as compared with a considerably lower 46.9% incidence of AA in schizophrenic patients nonhomozygous for the 2-2 allele (exact P = 0.0223). Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:187-191, 2000.

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.

Adenosine A1 receptor and bipolar affective disorder: systematic screening of the gene and association studies.

In the present study we sought to identify genetic variation in the adenosine A1 receptor (A1AR) gene on chromosome 1q31-32.1, which through alteration of protein function or level of expression might contribute to the genetic predisposition to bipolar affective disorder. We performed a systematic mutation scan of the whole coding sequence as well as 5' and 3' untranslated regions by means of single-strand conformation analysis. The region upstream to the coding sequence we investigated contains two functional promoters. Screening 42 patients with bipolar affective disorder, we detected 11 DNA sequence variants (48T/A, 267 + 275C/T, 805T/G, 1777C/A, 1827C/T, 1904C/T, 2126G/T, 2294insT, 2776C/T, 2777del36, 2819T/G). Determining the frequency of these variants in 42 anonymous blood donors, we observed a non-significant (P < 0.06) trend towards an underrepresentation of the 2126T variant in patients when compared to controls. On the other hand, the 2777del36 and the 2819G variant were not found among the controls. These findings were followed up in a large independent replication sample. However, we were not able to confirm the initial findings in the second sample. Our data suggest that genetically determined variation of the A1AR and its two promoters do not play a major role in the development of bipolar affective disorder.

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.

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.

Association study of the tryptophan hydroxylase gene and bipolar affective disorder using family-based internal controls.

The tryptophan hydroxylase (TPH) gene encodes for the rate-limiting enzyme of the serotonin metabolism and, therefore, has to be considered a major candidate for association studies in affective disorders. Recently, an association between this gene and bipolar affective disorder has been reported in a French population. We sought to replicate this finding in a German sample. Allele frequencies of a biallelic polymorphism (A218C) of the TPH gene were determined in 95 bipolar I patients and their parents. Preferential transmission of alleles from heterozygous parents to bipolar offspring was tested with the "transmission disequilibrium test" (TDT), which eliminates the contribution of population stratification to an association finding. Our sample yielded a power >90% to detect the originally reported effect. Neither allele 218A nor allele 218C were preferentially transmitted from heterozygous parents to bipolar offspring. Our results, therefore, do not support the hypothesis that the TPH gene is involved in the etiology of bipolar disorder.