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ABSTRACT: A range of psychological theories have been proposed to account for the experience of auditory hallucinations and delusions in schizophrenic patients. Most influential theories are those implicating the defective self-monitoring of inner speech. Some recent studies measured response bias independently of self-monitoring and found the results inconsistent with the defective self-monitoring model, but explained by an externalizing response bias. We aimed to investigate the role of attentional bias in external misattribution of source by modulating participant's endogenous expectancies. Comparisons were made between patients with paranoid schizophrenia (N=23) and matched healthy controls (N=23) who participated in two different versions of an audio-visual task, which differed based upon level of the cue predictiveness. The acoustic characteristic of voice was altered in half of the trials by shifting the pitch (distortion). Participants passively listened to recordings of single adjectives spoken in their own and another person's voice (alien) preceded by their own or another person's (alien) face and made self/non self judgments about the source. The patients showed increased error rates comparing to controls, when listening to the distorted self spoken words, misidentifying their own speech as produced by others. Importantly, patients made significantly more errors across all the invalid cue conditions. This suggests not only the presence of pathological misattribution bias, but also an inadequate balance between top-down and bottom-up attentional processes in the patients, which could be responsible for misattribution of the ambiguous sensory material.
Neuropsychologia 01/2011; 49(5):805-12. · 3.64 Impact Factor
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Schizophrenia Research 06/2008; Vol. 102(Issue 1, Sup. 2):p 121. · 4.75 Impact Factor
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ABSTRACT: Research based on pooling data from clinical trials suggests that it is possible to extrapolate from a CGI-S to a PANSS severity score and from the CGI-I to a PANSS percentage change score. This research has not been replicated nor examined in individual trials. This study aims to examine the feasibility of extrapolation from the CGI to the PANSS across and within 4 large clinical trials of antipsychotic medication.
Equipercentile linking is used to examine extrapolation (a) from CGI-S to PANSS severity ratings and (b) from CGI-I to PANSS percentage change (n=2698). Linking is conducted at baseline and after 2, 4, 6 and 8 weeks of treatment from ITT clinical trial participants with schizophrenia.
Across weeks 2, 4, 6 and 8, being considered 'not ill' according to the CGI-S corresponded to PANSS scores of 31-2. The relationship between the CGI-S and the PANSS followed an increasing trend, such that 'very mild' corresponded with 41-7, 'mild' corresponded with 55-62, 'moderate' corresponded with 71-7, 'marked' corresponded with 88-94, 'severe' corresponded with 105-110, and 'extremely severe' corresponded with 126-134. The relationship between CGI-I ratings and percentage change followed a linear trend, such that 'very much improved' corresponded to PANSS percentage change scores from 79 to 75, 'much improved' corresponded with 45 to 49, 'minimally improved' corresponded with 21 to 23, 'unchanged' corresponded with 2 to 3, 'minimally worse' corresponded with -15 to -20, 'much worse' corresponded with -44 to -51. Generally, within the trials the cut-off ranges identified overlapped within around 10 points of those found in the pooled analysis.
Despite trial heterogeneity, the results support the extrapolation from the CGI-I to PANSS percentage change. Extrapolation of the CGI-S to the PANSS is observed, except in the case of severe symptomatology which is rare. Collectively, the results support the extrapolation between the PANSS and CGI.
Schizophrenia Research 02/2008; 98(1-3):318-22. · 4.75 Impact Factor
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The International Journal of Neuropsychopharmacology 01/2008; 11:250-250. · 4.58 Impact Factor
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ABSTRACT: Experimental panic induction with cholecystokinin-tetrapeptide (CCK-4) has been established as a model to study the pathophysiology of panic disorder and might serve as a tool to asses the antipanic potential of novel anxiolytic compounds. However, assessment of CCK-4-induced panic does not follow consistent rules.
To provide a basis for the use of the CCK-4 model in proof-of-concept studies, we investigated CCK-4-induced panic according to different criteria in 85 healthy volunteers who underwent a CCK-4 bolus injection.
We assessed panicker/non-panicker ratios according to different panic criteria and explored whether differences in cardiovascular and neuroendocrine responses to CCK-4 paralleled subjective panic responses. Subjective panic responses were measured with the Acute Panic Inventory (API) and the Panic Symptom Scale (PSS). Heart rate, blood pressure, adrenocorticotropic hormone (ACTH) and cortisol were assessed concomitantly.
The API-derived panic rate was 10.6% higher than that derived from the PSS. CCK-4 induced an increase in heart rate, systolic blood pressure and ACTH/cortisol plasma levels, which did not differ between panickers and non-panickers.
The panic criterion applied appears to be of major importance for the panic rate achieved, whereas CCK-4-induced cardiovascular and hormonal alterations are not valuable as an objective "read out". The CCK-4 challenge might serve as a useful model to study putative anxiolytic effects of novel compounds during the early phase of drug development if the challenge procedure is carried out according to strictly comparable conditions.
Psychopharmacology 08/2007; 192(4):479-87. · 4.08 Impact Factor
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ABSTRACT: Despite the widespread use of the Brief Psychiatric Rating Scale (BPRS), the clinical meaning of its total score and cut-off values used to define treatment response are unclear.
To link the BPRS to Clinical Global Impression (CGI) ratings.
Equipercentile linking of BPRS and CGI ratings from seven drug trials in acutely ill patients with schizophrenia (n=1979).
'Mildly ill' according to the CGI approximately corresponded to a BPRS total score of 31, 'moderately ill'to a BPRS score of 41 and'markedly ill'to a BPRS score of 53.'Minimally improved'according to the CGI score was associated with percentage BPRS reductions of 24, 27 and 30% at weeks 1, 2 and 4, respectively. The corresponding numbers for a CGI rating of 'much improved' were 44, 53 and 58%.
The results provide a clearer understanding of how to interpret BPRS total and percentage reduction scores in clinical trials with patients acutely ill with schizophrenia who are experiencing positive symptoms.
The British Journal of Psychiatry 11/2005; 187:366-71. · 6.62 Impact Factor
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Peter Zill,
Thomas C Baghai, Rolf Engel,
Peter Zwanzger,
Cornelius Schüle,
Daniela Eser,
Stefanie Behrens,
Rainer Rupprecht,
Hans-Jürgen Möller,
Manfred Ackenheil,
Brigitta Bondy
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ABSTRACT: The pathophysiological mechanisms, as well as the molecular loci of antidepressant drug action have not yet been established, but recent models proposed that several adaptive mechanisms in signal transduction cascades beyond the receptor and reuptake systems are involved in antidepressant action and play an important role in the etiology of affective disorders. In this context, the dysbindin gene (dystrobrevin-binding-protein 1, DTNBP1), which was recently reported to be associated with schizophrenia seems to be an interesting candidate gene for affective disorders. Dysbindin is widely expressed in the human brain and binds to the dystrophin-associated protein complex (DPC) which appears to be involved in signal transduction pathways, which have been repeatedly investigated and described as altered or disturbed in affective disorders [McLeod et al. [2003: Psychopharmacol Bull 35:24-41]; Brambilla et al. [2003: Mol Psychiatry 8:721-737]]. Therefore, we investigated whether five SNPs in the dysbindin gene could be susceptibility factors in the ethiology of major depression or for the response to antidepressant treatment in a sample of 293 patients compared to 220 healthy controls. Applying single SNP evaluation, as well as haplotype analysis we could not detect an association between the dysbindin polymorphisms and major depression or the response to antidepressant treatment. In conclusion, our results suggest that SNPs in the dysbindin gene are unlikely to play a major role in the pathophysiology of major depression or are in linkage disequilibrium (LD) with a neighboring mutation or gene. Further analysis are needed to confirm these results.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 09/2004; 129B(1):55-8. · 3.70 Impact Factor
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Peter Zill,
Thomas C Baghai, Rolf Engel,
Peter Zwanzger,
Cornelius Schüle,
Christo Minov,
Stefanie Behrens,
Ronald Bottlender,
Markus Jäger,
Rainer Rupprecht,
Hans-Jürgen Möller,
Manfred Ackenheil,
Brigitta Bondy
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ABSTRACT: Noradrenergic dysfunction has been implicated in the development of affective disorders. beta-adrenergic receptors (betaARs) mediate the response to norephinephrine, are coupled to the cAMP signaling cascade, supposed to be altered in their density and/or sensitivity in depression, and down regulated in several brain regions after long term treatment with different but not all antidepressants. A recently identified functional polymorphism in the beta(1)-adrenergic receptor (G1165C) leading to the amino acid variation Gly389Arg was associated with an enhanced coupling to the stimulatory G(s)-protein and increased adenylyl cyclase activation, disturbances which are often observed in affective disorders. Therefore, we investigated whether this beta(1)AR polymorphism is associated with major depression or with the response to antidepressant treatment in a sample of 259 patients compared to 206 healthy controls. Although we could not detect an association between the beta(1)AR polymorphism and major depression we found a tendency for a relation between CC homozygosity and a better and even faster response to antidepressant treatment in those patients, which were treated with antidepressants affecting directly or indirectly the beta(1)AR system (tricyclic antidepressants, noradrenergic and serotonergic specific agents, selective noradrenaline reuptake inhibitors) determined by the HAMD and CGI score (P = 0.05). However, after correction for multiple testing (Bonferroni) these results did not remain significant. Nevertheless, these findings suggest that the presence of the C allele might be an indicator for antidepressant treatment response.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 08/2003; 120B(1):85-9. · 3.70 Impact Factor
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ABSTRACT: This study examines the alpha-subunit of the olfactory G-protein (G(olf)) as a possible candidate gene for bipolar disorder. The alpha-subunit of the G(olf) gene maps to a region on chromosome 18p that has been implicated in several linkage studies as a potential site of a bipolar disorder susceptibility loci.
We investigated whether two polymorphisms in the alpha-subunit of the G(olf) gene (A-->G in intron 3 and T-->G in intron 10) are associated with bipolar disorder in a sample of 149 bipolar patients under lithium treatment compared with 139 healthy controls using haplotype analysis.
There was no evidence for an association between the investigated polymorphisms in the G(olf) gene and bipolar disorders, as well as to response to lithium treatment or common side effects, like hand tremor, weight gain and cognitive dysfunction.
The results of the present study do not support the hypothesis that the G(olf) gene is a major susceptibility factor for bipolar disorders.
Psychiatric Genetics 06/2003; 13(2):65-9. · 2.58 Impact Factor
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ABSTRACT: Growing evidence suggests that G-proteins may be involved in pathogenesis and treatment of affective disorders. Several studies have reported altered levels and/or activities of stimulatory G-proteins in depression. The aim of this study was to investigate whether a polymorphism in the stimulatory alpha subunit of G-proteins (T/C point mutation in exon 5; ATT --> ATC at codon 131) is associated with major depression or response to antidepressant treatment. Therefore, we performed a case-control association study with 212 depressive patients and 137 healthy, unrelated controls. There was no evidence for an association between the investigated polymorphism in the G(alpha)(s) gene and major depression, as well as to treatment response. The results of our study are in concordance with recently published findings which do not support the hypothesis that the gene for the stimulatory alpha subunit of G-proteins is a major susceptibility factor in the pathophysiology of major depression.
American Journal of Medical Genetics 07/2002; 114(5):530-2.
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ABSTRACT: It is well established that G-proteins represent essential regulatory components in transmembrane signaling. The alpha subunit of the olfactory G-protein Golf (GNAL) maps to a region on chromosome 18 where linkage to affective disorders has been reported, as well as a parent-of-origin effect in affective disorders with some markers near the locus for the alpha subunit of the Golf gene. We investigated whether two polymorphisms in the alpha subunit of the Golf gene (A-->G in intron 3, and T-->G in intron 10) are associated with major depression in 176 major depressive patients compared with 145 healthy control subjects, and additionally tested for a parent-of-origin effect in separated gender groups. In the control group, we found a significant increase in the G-allele frequency of the intron 3 polymorphism in females (P=0.0036, odds ratio=2.13, 95% confidence interval=1.29-3.54, Fisher's Exact Test). In patients, we found a similar tendency for higher G-allele frequencies in females. Concerning the intron 10 polymorphism, no differences in the genotype or allele frequencies were detectable for any of the separated gender groups. Also, the total patient and control groups showed no differences in allele or genotype frequencies for any of the investigated polymorphisms. The results of this study agree with the reported parent-of-origin effects on chromosome 18, but do not support the hypothesis that the Golf gene is a major susceptibility factor for major depression.
Psychiatric Genetics 04/2002; 12(1):17-22. · 2.58 Impact Factor
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Peter Zill, Rolf Engel,
Thomas C Baghai,
Georg Juckel,
Thomas Frodl,
Florian Müller-Siecheneder,
Peter Zwanzger,
Cornelius Schüle,
Christo Minov,
Stefanie Behrens,
Rainer Rupprecht,
Ulrich Hegerl,
Hans Jürgen Möller,
Brigitta Bondy
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ABSTRACT: Disturbances in the noradrenergic neurotransmission system have been implicated in the etiology of mood disorders. The norepinephrine transporter (NET) is a main target of antidepressant action and was shown to be dysregulated in major depression. Despite the clinical and physiological significance of NET gene regulation, little is known about the transcriptional control mechanisms governing its expression. Since it is well established that affective disorders have a genetic component with many genes of small effect contributing to the genetic susceptibility of depression, the NET gene is an interesting candidate gene for affective disorders. In a search for polymorphisms or mutations in the 5' flanging region of the NET gene we sequenced approximately 1000 bp upstream of the first codon in the NET gene promoter in 100 patients with major depression and 100 healthy controls. We identified a so far unknown T --> C polymorphism 182 bp upstream of the start codon in a transcriptional relevant region. In a case control association study we investigated the newly identified T-182C polymorphism and an already known G1287A polymorphism in exon 9 of the NET gene in a sample of 193 patients with major depression and 136 healthy, non-related controls. No statistical significant differences between patients and controls were found for any of the analyzed polymorphisms, either in the genotype distribution or in the allele frequencies. Our results suggest that the investigated polymorphisms are not major susceptibility factors in the etiology of major depression.
Neuropsychopharmacology 04/2002; 26(4):489-93. · 7.99 Impact Factor
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ABSTRACT: Two recently described polymorphisms in the promoter region of the apolipoprotein E (APOE), the −491A7T and Th1/E47csT/G
polymorphism, have been suggested to be associated with an increased risk for Alzheimer's disease (AD) independent from the
APOE ɛ4 carrier status. We studied the association between the APOE ɛ4 polymorphism and the −491A/T and Th1E47csT/G polymorphisms
in a sample of 118 healthy, non-demented controls and 239 consecutively recruited gerontopsychiatric patients diagnosed as:
Alzheimer's disease (N = 89), age mild cognitive impairment (N = 32), memory complainers without any congitive deficit (N
= 54) and depression/other psychiatric disorders (N = 64), to test whether the investigated polymorphisms have a high enough
selectivity and specificity to distinguish between the different gerontopsychiatric disorders to differentiate AD genetically
from other forms of dementia, respectively. Also a possible association with the APOE ɛ4 polymorphism was examined. We found
a statistically significant association between the APOE ɛ4 allele and Alzheimer's disease (p = 0.0001) and age associated
memory impairment (p = 0.006). Our study failed to show an association between the promoter polymorphisms −491A/T and Th1E47csT/G
in the APOE gene and gerontopsychiatric disorders either alone or in relationship to the APOE ɛ4 polymorphism. However, if
we combine our results with three previous published positive reports there seems to be an association between the −491A/T
polymorphism and AD, though its size is less than found in the original publication.
European Archives of Psychiatry and Clinical Neuroscience 02/2001; 251(1):24-28. · 3.49 Impact Factor
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ABSTRACT: 1. To evaluate the influence of beta-blockers and minor tranquilizers on autonomous stress response, 40 healthy subjects selected with regard to personality traits were randomly assigned to 5 groups.2. Mental arithmetic induced the most pronounced increase in heart rate (HR), blood pressure and epinephrine secretion.3. Beta-blockers reduced HR increases due to mental stress, whereas the minor tranquilizer reduced skin conductance level throughout the whole trial.4. Our data provide evidence that different structured situations induce specific response patterns that are differentially modified by beta-blockers and minor tranquilizer.
Progress in Neuro-Psychopharmacology and Biological Psychiatry.
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