Theory of mind, emotion recognition, delusions and the quality of the therapeutic relationship in patients with psychosis - a secondary analysis of a randomized-controlled therapy trial.

BACKGROUND: Cognitive models of psychosis postulate an important role of Theory of mind (ToM) in the formation and maintenance of delusions, but research on this plausible conjecture has gathered conflicting findings. In addition, it is still an open question whether problems in emotion recognition (ER) are associated with delusions. We examined the association of problems in ToM and ER with different aspects of delusions in a large sample of patients with psychosis enrolled in a therapy trial. This also enabled us to explore the possible impact of ToM and ER on one part of patients' social life: the quality of their therapeutic relationship. METHODS: Patients with psychotic disorders and delusions and/or hallucinations (n = 185) and healthy controls (n = 48) completed a ToM picture sequencing task and an ER task. Subsequently, patients were enrolled in a randomized-controlled Cognitive Behavior Therapy (CBT) trial (ISRCTN29242879). Patients and therapists rated the quality of the therapeutic relationship during the first five sessions of therapy. RESULTS: In comparison to controls, patients were impaired in both ToM and ER. Patients with deficits in ER experienced more severe delusional distress, whereas ToM problems were not related to delusions. In addition, deficits in ER predicted a less favorable therapeutic relationship and interactional problems viewed by the therapist. Impaired ER also moderated (increased) the negative influence of delusions on the therapeutic relationship and interactional difficulties viewed by the therapist. CONCLUSIONS: Cognitive models on the formation and maintenance of delusions should consider ER as a potential candidate that might be related to the formation and maintenance of delusional distress, whereas problems in ToM might not be directly related to delusions and secondary dimensions of delusions. In addition, problems in ER in patients with psychosis might have an impact on the quality of the therapeutic relationship and patients with problems in ER are more likely to be viewed as problematic by their therapists. Nevertheless, training ER might be a way to improve the quality of the therapeutic relationship and potentially the effectiveness of CBT or other interventions for patients with psychosis.

Problems in measuring the JTC-bias in patients with psychotic disorders with the fish task: a secondary analysis of a baseline assessment of a randomized controlled trial.

BACKGROUND: The jumping to conclusions bias (JTC) is considered to be an important causal factor in theoretical models for the formation and maintenance of delusions. However, recent meta-analytic findings show a rather equivocal pattern of results regarding associations between JTC and delusions. Thus, the present study aims to investigate in a large sample whether the JTC-bias is more pronounced in patients with psychotic disorders in comparison to controls and whether the JTC bias is associated with a more severe delusional conviction, persecutory delusions, and positive symptoms in general. METHODS: Patients with psychotic disorders (n = 300) enrolled in a therapy trial and healthy controls (n = 51) conducted a variant of the beads task (fish task) as a measure for the JTC-bias at the start of the trial. Further, clinical interviews were used to assess patients' delusional severity and delusional conviction. RESULTS: There were no statistically significant differences between patients with psychotic disorders (with 53% displaying the JTC-bias) and controls (41%). Furthermore, there were no statistically significant correlations between JTC measures and persecutory delusions, delusional conviction, and positive symptoms. CONCLUSIONS: We found no differences in JTC between patients with psychotic disorders and healthy controls, which is in part in line with meta-analytic findings using a wide range of JTC task variants. Interestingly, patients with psychotic disorders displayed JTC rates commonly found in the literature, while healthy control subjects showed an unexpectedly high level of JTC. The task variant we used in the present study (fish task) is discussed as a potential reason for our results, as it may induce a more deliberative reasoning style in controls as compared to the traditional beads task. Furthermore, possible implications for the measurement of the JTC-bias, in general, are discussed. TRIAL REGISTRATION: ISRCTN29242879 ( isrctn.com ), date of registration: April 12th 2006, retrospectively registered.

Nicotine enhances antisaccade performance in schizophrenia patients and healthy controls.

Nicotine has been proposed to be a cognitive enhancer, particularly in schizophrenia patients. So far, the published studies of nicotine effects on antisaccade performance in schizophrenia patients only tested participants who were deprived smokers. Thus, we aimed to test both smoking and non-smoking patients as well as healthy controls in order to extend previous findings. Moreover, we employed a paradigm using standard and delayed trials. We hypothesized that, if nicotine is a genuine cognitive enhancer, its administration would improve antisaccade performance both in smoking and non-smoking participants. A total of 22 patients with schizophrenia (12 smokers and 10 non-smokers) and 26 controls (14 smokers and 12 non-smokers) completed the study. The effects of a nicotine patch (14 mg for smokers, 7 mg for non-smokers) on antisaccade performance were tested in a randomized, double-blind, placebo-controlled, cross-over trial. Schizophrenia patients made significantly more antisaccade errors than controls (p = 0.03). Both patients and controls made fewer antisaccade errors in the delayed trials than in the standard trials (p < 0.0001). Nicotine significantly reduced antisaccade error rate in the standard trials, but not in the delayed trials (p = 0.02). Smoking status did not influence the nicotine effect on antisaccade error rate (p = 0.10) indicating an equal procognitive effect of nicotine in smokers and non-smokers. Overall the present findings indicate that beneficial effects of nicotine on antisaccade performance are not confined to smoking schizophrenia patients. Instead, the findings likely represent genuine nicotine-induced enhancement of cognitive performance.

The functional coding variant Asn107Ile of the neuropeptide S receptor gene (NPSR1) is associated with schizophrenia and modulates verbal memory and the acoustic startle response.

Recently, the neuropeptide S (NPS) neurotransmitter system has been identified as a promising psychopharmacological drug target given that NPS has shown anxiolytic-like and stress-reducing properties and memory-enhancing effects in rodent models. NPS binds to the G-protein-coupled receptor encoded by the neuropeptide S receptor gene (NPSR1). A functional variant within this gene leads to an amino-acid exchange (rs324981, Asn107Ile) resulting in a gain-of-function in the Ile107 variant which was recently associated with panic disorder in two independent studies. A potential psychopharmacological effect of NPS on schizophrenia psychopathology was demonstrated by showing that NPS can block NMDA antagonist-induced deficits in prepulse inhibition. We therefore explored a potential role of the NPSR1 Asn107Ile variation in schizophrenia. A case-control sample of 778 schizophrenia patients and 713 healthy control subjects was successfully genotyped for NPSR1 Asn107Ile. Verbal declarative memory and acoustic startle response were measured in subsamples of the schizophrenia patients. The case-control comparison revealed that the low-functioning NPSR1 Asn107 variant was significantly associated with schizophrenia (OR 1.19, p=0.017). Moreover, specifically decreased verbal memory consolidation was found in homozygous Asn107 carriers while memory acquisition was unaffected by NPSR1 genotype. The schizophrenia patients carrying the Ile107 variant demonstrated significantly reduced startle amplitudes but unaffected prepulse inhibition and habituation. The present study confirms findings from rodent models demonstrating an effect of NPS on memory consolidation and startle response in schizophrenia patients. Based on these findings, we consider NPS as a promising target for antipsychotic drug development.

A promoter variant of SHANK1 affects auditory working memory in schizophrenia patients and in subjects clinically at risk for psychosis.

Mutations in postsynaptic scaffolding genes contribute to autism, thus suggesting a role in pathological processes in neurodevelopment. Recently, two de novo mutations in SHANK3 were described in schizophrenia patients. In most cases, abnormal SHANK3 genotype was also accompanied by cognitive disruptions. The present study queries whether common SHANK variants may also contribute to neuropsychological dysfunctions in schizophrenia. We genotyped five common coding or promoter variants located in SHANK1, SHANK2 and SHANK3. A comprehensive test battery was used to assess neuropsychological functions in 199 schizophrenia patients and 206 healthy control subjects. In addition, an independent sample of 77 subjects at risk for psychosis was analyzed for replication of significant findings. We found the T allele of the SHANK1 promoter variant rs3810280 to lead to significantly impaired auditory working memory as assessed with digit span (12.5 ± 3.6 vs. 14.8 ± 4.1, P < .001) in schizophrenia cases, applying strict Bonferroni correction for multiple testing. This finding was replicated for forward digit span in the at-risk sample (7.1 ± 2.0 vs. 8.3 ± 2.0, P = .044). Previously, altered memory functions and reduced dendritic spines and postsynaptic density of excitatory synapses were reported in SHANK1 knock-out mice. Moreover, the atypical neuroleptic clozapine was found to increase SHANK1 density in rats. Our findings suggest a role of SHANK1 in working memory deficits in schizophrenia, which may arise from neurodevelopmental changes to prefrontal cortical areas.

Novel schizophrenia risk gene TCF4 influences verbal learning and memory functioning in schizophrenia patients.

BACKGROUND: Recently, a role of the transcription factor 4 (TCF4) gene in schizophrenia has been reported in a large genome-wide association study. It has been hypothesized that TCF4 affects normal brain development and TCF4 has been related to different forms of neurodevelopmental disorders. Schizophrenia patients exhibit strong impairments of verbal declarative memory (VDM) functions. Thus, we hypothesized that the disease-associated C allele of the rs9960767 polymorphism of the TCF4 gene led to impaired VDM functioning in schizophrenia patients. METHOD: The TCF4 variant was genotyped in 401 schizophrenia patients. VDM functioning was measured using the Rey Auditory Verbal Learning Test (RAVLT). RESULTS: Carriers of the C allele were less impaired in recognition compared to those carrying the AA genotype (13.76 vs. 13.06; p = 0.049). Moreover, a trend toward higher scores in patients with the risk allele was found for delayed recall (10.24 vs. 9.41; p = 0.088). The TCF4 genotype did not influence intelligence or RAVLT immediate recall or total verbal learning. CONCLUSION: VDM function is influenced by the TCF4 gene in schizophrenia patients. However, the elevated risk for schizophrenia is not conferred by TCF4-mediated VDM impairment.

Why do bad things happen to me? Attributional style, depressed mood, and persecutory delusions in patients with schizophrenia.

Theoretical models postulate an important role of attributional style (AS) in the formation and maintenance of persecutory delusions and other positive symptoms of schizophrenia. However, current research has gathered conflicting findings. In a cross-sectional design, patients with persistent positive symptoms of schizophrenia (n = 258) and healthy controls (n = 51) completed a revised version of the Internal, Personal and Situational Attributions Questionnaire (IPSAQ-R) and assessments of psychopathology. In comparison to controls, neither patients with schizophrenia in general nor patients with persecutory delusions (n = 142) in particular presented an externalizing and personalizing AS. Rather, both groups showed a "self-blaming" AS and attributed negative events more toward themselves. Persecutory delusions were independently predicted by a personalizing bias for negative events (beta = 0.197, P = .001) and by depression (beta = 0.152, P = .013), but only 5% of the variance in persecutory delusions could be explained. Cluster analysis of IPSAQ-R scores identified a "personalizing" (n = 70) and a "self-blaming" subgroup (n = 188), with the former showing slightly more pronounced persecutory delusions (P = .021). Results indicate that patients with schizophrenia and patients with persecutory delusions both mostly blamed themselves for negative events. Nevertheless, still a subgroup of patients could be identified who presented a more pronounced personalizing bias and more severe persecutory delusions. Thus, AS in patients with schizophrenia might be less stable but more determined by individual and situational characteristics that need further elucidation.

Multimodal motion processing in area V5/MT: evidence from an artificial class of audio-visual events.

Audio-visual integration in the human brain influences perception and precision of motor tasks. We tested audio-visual integration during height estimation when presenting video clips of counter movement jumps (CMJ), using sparse sampling fMRI at 3T. Employing the technique of "sonification", we created artificial auditory-visual motion events by transforming the ground reaction force of the CMJs into the auditory domain, modulating frequency and amplitude of the standard pitch "A" (440 Hz). We combined these "sonificated" movements with either concordant or discordant visual movement displays. We hypothesized that processing of concordant audio-visual stimuli would enhance neural activity in audio-visual integration areas. Therefore, four conditions were compared: 1. unimodal visual, 2. unimodal auditory, 3. auditory+visual concordant, and 4. auditory+visual discordant. The unimodal conditions, when compared against each other, resulted in expected activation maxima in primary visual and auditory cortex, respectively. Enhanced activation was found in area V5/MT bilaterally for the concordant multimodal, as compared to both unimodal, conditions. This effect was specific for the concordant bimodal condition, as evidenced by a direct comparison between concordant and discordant bimodal conditions. Using "sonification", we provide evidence that area V5/MT is modulated by concordant auditory input, albeit the artificial nature of the stimuli, which argues for a role of this region in multimodal motion integration, beyond the pure visual domain. This may explain previous behavioral evidence of facilitatory effects exerted by auditory motion stimuli on the perception of visual motion, and may provide the basis for future applications in motor learning and rehabilitation.