Evaluation of the 'Jumping to conclusions' bias in different subgroups of the at-risk mental state: from cognitive basic symptoms to UHR criteria.

BACKGROUND: Patients with psychosis display the so-called 'Jumping to Conclusions' bias (JTC) - a tendency for hasty decision-making in probabilistic reasoning tasks. So far, only a few studies have evaluated the JTC bias in 'at-risk mental state' (ARMS) patients, specifically in ARMS samples fulfilling 'ultra-high risk' (UHR) criteria, thus not allowing for comparisons between different ARMS subgroups. METHOD: In the framework of the PREVENT (secondary prevention of schizophrenia) study, a JTC task was applied to 188 patients either fulfilling UHR criteria or presenting with cognitive basic symptoms (BS). Similar data were available for 30 healthy control participants matched for age, gender, education and premorbid verbal intelligence. ARMS patients were identified by the Structured Interview for Prodromal Symptoms (SIPS) and the Schizophrenia Proneness Instrument - Adult Version (SPI-A). RESULTS: The mean number of draws to decision (DTD) significantly differed between ARM -subgroups: UHR patients made significantly less draws to make a decision than ARMS patients with only cognitive BS. Furthermore, UHR patients tended to fulfil behavioural criteria for JTC more often than BS patients. In a secondary analysis, ARMS patients were much hastier in their decision-making than controls. In patients, DTD was moderately associated with positive and negative symptoms as well as disorganization and excitement. CONCLUSIONS: Our data indicate an enhanced JTC bias in the UHR group compared to ARMS patients with only cognitive BS. This underscores the importance of reasoning deficits within cognitive theories of the developing psychosis. Interactions with the liability to psychotic transitions and therapeutic interventions should be unravelled in longitudinal studies.

Investigation of metamemory functioning in the at-risk mental state for psychosis.

BACKGROUND: Metamemory describes the monitoring and knowledge about one's memory capabilities. Patients with schizophrenia have been found to be less able in differentiating between correct and false answers (smaller confidence gap) when asked to provide retrospective confidence ratings in previous studies. Furthermore, higher proportions of very-high-confident but false responses have been found in this patient group (high knowledge corruption). Whether and how these biases contribute to the early pathogenesis of psychosis is yet unclear. This study thus aimed at investigating metamemory function in the early course of psychosis. METHOD: Patients in an at-risk mental state for psychosis (ARMS, n = 34), patients with a first episode of psychosis (FEP, n = 21) and healthy controls (HCs, n = 38) were compared on a verbal recognition task combined with retrospective confidence-level ratings. RESULTS: FEP patients showed the smallest confidence gap, followed by ARMS patients, followed by HCs. All groups differed significantly from each other. Regarding knowledge corruption, FEP patients differed significantly from HCs, whereas a statistical trend was revealed in comparison of ARMS and FEP groups. Correlations were revealed between metamemory, measures of positive symptoms and working memory performance. CONCLUSIONS: These data underline the presence of a metamemory bias in ARMS patients which is even more pronounced in FEP patients. The bias might represent an early cognitive marker of the beginning psychotic state. Longitudinal studies are needed to unravel whether metacognitive deficits predict the transition to psychosis and to evaluate therapeutic interventions.

Obsessive-compulsive symptoms in at-risk mental states for psychosis: associations with clinical impairment and cognitive function.

OBJECTIVE: Obsessive-compulsive symptoms (OCS) constitute a major comorbidity in schizophrenia. Prevalence estimations of OCS for patients with at-risk mental states (ARMS) for psychosis vary largely. It is unclear how ARMS patients with or without comorbid OCS differ regarding general psychosocial functioning, psychotic and affective symptoms and neurocognitive abilities. METHOD: At-risk mental states patients (n = 233) from the interventional trial PREVENT (Secondary Prevention of Schizophrenia) were stratified according to the presence or absence of comorbid OCS and compared on several clinical variables. RESULTS: Patients, who fulfilled the criteria for obsessive-compulsive disorder (OCD) or presented with subclinical OCS (ARMSposOCS sample), did not significantly differ from patients without OCS (ARMSnegOCS) with regard to gender, age, premorbid verbal intelligence and levels of education. Furthermore, similar severity of depressive syndromes, basic cognitive, attenuated psychotic and brief limited intermittent psychotic symptoms were found. However, ARMSposOCS patients showed more impairment of psychosocial functioning and higher general psychopathology. In contrast, they scored higher in cognitive tasks measuring working memory and immediate verbal memory. CONCLUSION: Findings extend upon previous results due to the multidimensional assessment. Subsequent longitudinal studies might elucidate how comorbid OCS influence differential treatment response, especially to cognitive behavioural interventions and the transition rates to psychosis.

Antiserotonergic antipsychotics are associated with obsessive-compulsive symptoms in schizophrenia.

BACKGROUND: Epidemiological investigations show that up to 30% of schizophrenic patients suffer from obsessive-compulsive symptoms (OCS) associated with negative impact on the general prognosis. It has been proposed that antiserotonergic second-generation antipsychotics (SGAs) might induce OCS, but investigations of large samples integrating psychopathology, neuropsychology and psychopharmacology are missing. METHOD: We stratified 70 patients with schizophrenia according to their mode of antipsychotic treatment: clozapine and olanzapine (group I) compared with aripiprazole and amisulpride (group II). The groups were matched according to age, sex, educational levels and severity of the psychotic disorder (Positive and Negative Syndrome Scale). As the primary endpoint, we evaluated OCS severity (Yale-Brown Obsessive-Compulsive Scale). RESULTS: OCS were significantly more prevalent and severe in group I, in which OCS severity correlated with dosage of clozapine and duration of treatment. Pronounced cognitive deficits in group I were found in visuospatial perception and visual memory (Wechsler Adult Intelligence Scale-Revised block design, Rey-Osterrieth Complex Figure Test), impulse inhibition (go/no-go test), higher perseveration scores (Wisconsin Card Sorting Test) and reduced set-shift abilities (Trail Making Test Part B, Set-shift Task). These cognitive domains correlated with OCS severity. CONCLUSIONS: OCS in schizophrenia are associated with antiserotonergic SGA treatment, but longitudinal studies have to prove causality. Before starting treatment with antiserotonergic SGAs, specific neurocognitive domains should be evaluated, as visuospatial learning and impulse inhibition performance might allow early detection of OCS secondary to antipsychotic treatment in schizophrenia.

[Polypharmacy in schizophrenia]. / Polypharmazie bei schizophrenen Psychosen.

BACKGROUND: While most guidelines recommend monotherapy with second-generation antipsychotics (SGA) in schizophrenia, the combined application of multiple psychotropic agents is very common, especially in treatment-refractory cases. METHODS: This review summarizes the evidence of combined antipsychotic treatment strategies and the augmentation of antipsychotics with mood stabilizers, antidepressants and experimental substances, based on publications accessible in public databases (Medline/Ovid, Google, http://www.clinicaltrials.gov) up to October 2009. RESULTS: Polypharmacy aims to address several aspects of treatment resistance and side effects of antipsychotics. Some evidence supports the augmentation of antipsychotics with antidepressants for negative symptoms and comorbid major depressive episodes. The add-on of lithium and mood stabilizers lacks compelling evidence but might be beneficial for specific subgroups. For treatment-resistant cognitive symptoms, cognitive re-mediation seems most promising as no pharmacological add-on strategy has gained convincing evidence so far. Acute dystonic movements should be treated with anticholinergic agents while agitation and anxiety might respond to short-term application of benzodiazepines. Treatment-resistant positive and/or negative symptoms should primarily lead to clozapine monotherapy; the add-on of a second SGA may be considered in single cases. CONCLUSIONS: In general, rigorous data on combination therapy in schizophrenia are rare, and further randomized controlled trials (RCT), naturalistic and head-to-head-studies are necessary.

Long-term efficacy and tolerability of clozapine combined with ziprasidone or risperidone.

INTRODUCTION: Treatment resistance in schizophrenia often leads to add-on of atypical antipsychotics to clozapine. METHODS: In a randomized trial, we recently obtained evidence for comparable efficacy and differential side effects of clozapine in combination with ziprasidone (CZ, N=12) versus risperidone (CR, N=12). Here, we present the open-label, long-term evaluations of these patients after 26 and 52 weeks. RESULTS: Sustained improvements of psychopathology as assessed by PANSS (positive and negative syndrome scale), SANS (scale for the assessment of negative symptoms), and HAMD (Hamilton depression scale) were documented in both subsamples being treated according to protocol, while dropouts reduced the study sample after 26 (CZ: reduced by -4; CR: -2) and 52 weeks (CZ: -0; CR: -5). We observed a slight increase of akathisia in the CZ group whereas general clozapine-associated side effects improved. DISCUSSION: The combinations of clozapine with ziprasidone or risperidone exhibit long-term efficacy, but the level of evidence is limited. Further head-to-head comparisons of atypical antipsychotics as add-on to clozapine are necessary.

Duloxetine for major depressive episodes in the course of psychotic disorders: an observational clinical trial.

Patients with psychotic disorders often suffer from intercurrent major depressive episodes (MDE). Case reports suggested successful antidepressive treatment with duloxetine, a selective dual reuptake inhibitor of serotonin and norepinephrine. We initiated this open prospective clinical trial to evaluate efficacy, safety and tolerability of this approach. Patients with a psychotic lifetime diagnosis suffering from mildly severe MDE were treated with duloxetine over a period of 6 weeks. We evaluated effects on mood, monitored the psychotic psychopathology and assessed side effects, basal clinical and pharmacological parameters. Twenty patients were included and experienced a significant improvement of their MDE during the observation period (Calgary Depression Scale for Schizophrenia and Hamilton Depression Scale). Psychotic positive symptoms remained stably absent, while negative syndrome and global psychopathology considerably improved (Positive and Negative Syndrome Scale). In general, the treatment was well tolerated, serum prolactin levels stayed unchanged, but pharmacokinetic interactions with a number of antipsychotic agents were observed. This open prospective evaluation showed antidepressive efficacy of duloxetine in patients with co-morbid psychotic disorders. With regard to the psychotic disorder, the treatment appears to be safe and well tolerable. Further investigations should involve a randomized control group.

DNA fragments in the blood plasma of cancer patients: quantitations and evidence for their origin from apoptotic and necrotic cells.

Increased levels of DNA fragments have frequently been found in the blood plasma of cancer patients. Published data suggest that only a fraction of the DNA in blood plasma is derived from cancer cells. However, it is not known how much of the circulating DNA is from cancer or from noncancer cells. By quantitative methylation-specific PCR of the promoter region of the CDKN2A tumor suppressor gene, we were able to quantify the fraction of plasma DNA derived from tumor cells. In the plasma samples of 30 unselected cancer patients, we detected quantities of tumor DNA from only 3% to as much as 93% of total circulating DNA. We investigated possible origins of nontumor DNA in the plasma and demonstrate here a contribution of T-cell DNA in a few cases only. To investigate the possibility that plasma DNA originates from apoptotic or necrotic cells, we performed studies with apoptotic (staurosporine) and necrotic (staurosporine plus oligomycin) cells in vitro and with mice after induction of apoptotic (anti-CD95) or necrotic (acetaminophen) liver injury. Increasing amounts of DNA were found to be released in the supernatants of cells and in the blood plasma samples of treated animals. A clear discrimination of apoptotic and necrotic plasma DNA was possible by gel electrophoresis. The same characteristic patterns of DNA fragments could be identified in plasma derived from different cancer patients. The data are consistent with the possibility that apoptotic and necrotic cells are a major source for plasma DNA in cancer patients.

Detection and molecular typing of Borrelia burgdorferi sensu lato in Ixodes ricinus ticks and in different patient samples from southwest Germany.

The prevalence of different genospecies of Borrelia burgdorferi sensu lato in infected ticks could be a determinant for the risk of acquiring Lyme borreliosis (LB) and its clinical presentation. A total of 7373 ticks and 2761 samples from LB patients from the same area in southwest Germany were analyzed by PCR to assess the frequency of the occurrence of LB-associated genospecies. Fifteen percent of the tick samples and 19% of the human samples were found positive for the presence of B. burgdorferi sensu lato. Further identification of 1106 B. burgdorferi sensu lato positive tick samples by reverse line blotting and 125 positive patient samples by nested PCR using species-specific primers revealed the occurrence of B. afzelii, B. burgdorferi sensu stricto, B. garinii and B. valaisiana. Both single-species and mixed infections were noted and a similar distribution of the different genospecies was found in ticks compared with human samples. It was also the purpose of this study to obtain more information about a possible correlation between the distribution of Borrelia species and clinical syndromes of LB. Skin biopsies of 59 patients with acrodermatitis chronica atrophicans and cerebrospinal fluid samples from 78 patients with possible neuroborreliosis were analyzed. In conclusion, the distribution of the different genospecies in ticks is the decisive factor for the occurrence of the different Borrelia genospecies in samples from LB patients. Borrelia afzelii is the predominant genospecies in all kind of samples from the observed area and there seems to be no association of particular Borrelia genospecies with distinct clinical manifestations of LB.

[QT syndrome: new diagnostic possibilities]. / QT-Syndrome: Neue diagnostische Möglichkeiten.

Electrocardiographic and clinical characteristics are currently used as diagnostic criteria for the long QT-syndrome. In borderline electrocardiographic findings associated with unclear syncope, it is often difficult to ensure or exclude long QT-syndrome. Schwartz and coworkers therefore created a point system as a guide in clinical decision making. In recent years genetic diagnostics have entered the arena of long-QT assessment. Aside from new insights into the pathophysiology of the long QT-disorder, it is expected that genetic diagnostics will offer substantial help to ascertain long QT-syndrome in patients with borderline electrocardiographic and clinical findings and improve risk stratification in long-QT family members. Performing linkage analysis, coupling of autosomal-dominant congenital long QT-syndrome (Romano-Ward Syndrome) to chromosomes 11 (LQT1/11p15.5), 3 (LQT3/3p21), 7 (LQT2/7q35), and 4 (LQT4/4q25-27) was demonstrated. More recently, the disease genes in long QT-syndrome 1, 2, and 3 could be identified. Analysis of the base-pair sequence allowed detection of several different mutations in different families illustrating genetic heterogeneity. Aside from diagnostic aspects, molecular genetics may also guide pharmacological therapy by identifying the specific ion-channel disorder leading to QT-prolongation and sudden death.

Detection of mutations in human genes by a new rapid method: cleavage fragment length polymorphism analysis (CFLPA).

Cleavage fragment length polymorphism analysis with silver staining visualization (CFLPA-SS) was used for the detection of mutations previously detected by single strand conformation (SSCA) or heteroduplex analyses (HA); in order to assess this new method for mutation screening. The analysed mutations include single nucleotide transitions, transversions, a deletion and a duplication in the following genes: CFTR (cystic fibrosis transmembrane conductance regulator), COL4A5 (collagen type 4 alpha 5 chain), PKD1 (polycystic kidney disease 1), and FGFR3 (fibroblast growth factor receptor 3). Peripheral blood leukocyte genomic DNA was isolated, amplified by polymerase chain reaction (PCR), and then cleaved by Cleavase I enzyme at different temperatures. Electrophoresis of the fragments on denaturing polyacrylamide gel was followed by silver staining for 1 min. All 13 mutations investigated were reproducibly detected. CFLPA-SS proved to be a reliable method for mutation detection and more rapid than SSCA and HA.

A common polymorphism in exon 46 of the human autosomal dominant polycystic kidney disease 1 gene (PKD1).

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common single gene diseases in humans. We have identified a synonymous T to C transition polymorphism in exon 46 of the PKD1 gene (12838T-->C, Pro4209Pro). The polymorphism was present with similar frequencies in ADPKD patients and unaffected individuals. The heterozygosity, determined in 89 Italian individuals, was 0.347. The frequency of the rarer allele was 0.222. This polymorphism is easy to determine as it abolishes a naturally occurring Ddel restriction site. The availability of an additional intragenic marker in the PKD1 gene will improve the accuracy of linkage studies in ADPKD families.

Structure of the yeast isoleucyl-tRNA synthetase gene (ILS1). DNA-sequence, amino-acid sequence of proteolytic peptides of the enzyme and comparison of the structure to those of other known aminoacyl-tRNA synthetases.

The ILS1 gene encoding for cytoplasmic isoleucyl-tRNA synthetase from Saccharomyces cerevisiae was subcloned from a 5.4-kb insert of the shuttle vector YEp13 to M13mp8 and M13mp9. Nucleotide sequence analysis of a 4.3-kb BamHI-HpaI fragment revealed a single open reading frame from which we deduced the amino-acid sequence of the enzyme. Independently obtained amino-acid sequence information from ten tryptic peptides of the purified enzyme confirmed the gene-derived structure. The enzyme is comprised of 1073 amino-acids consistent with earlier determinations of its molecular mass. The codon usage of ILS1 is typical of abundant yeast proteins. A significant homology to E. coli isoleucyl- and valyl-tRNA synthetases as well as to yeast valyl-tRNA synthetase was detected. The characteristic amino-acid residues of the aminoacyl-adenylate site and of the potential binding site of the 3'-end of tRNA found in other synthetases are present in the structure.