Michael Dettling - Academia.edu (original) (raw)
Papers by Michael Dettling
European Psychiatry, 2014
Key points • Schizophrenia is an umbrella term for a group of disorders that present with a commo... more Key points • Schizophrenia is an umbrella term for a group of disorders that present with a common set of symptoms; subtypes are diverse and reflect varied prognoses and treatment responses. • ICD 10 and the DSM IV are the current diagnostic schedules used for diagnosing schizophrenia. DSM V is in final stages of revision and is likely to be published in the fall of 2013. ICD is also being revised, and ICD 11 is likely to be published in 2014. • Development of schizophrenia is governed by a multifactorial model that includes genetic, neurodevelopmental, social, and psychological triggers. • Whether atypical antipsychotics (new generation) are superior to typical ones (old generation) in regard to efficacy and side-effect profiles continues to be debated. • Schizophrenia is more than an illness that affects individuals; it affects families and, at times, communities. Historical note and nomenclature Historically, schizophrenia can be traced back to old Pharaonic Egypt as far as the s...
Schizophrenia Research, 2015
Schizophrenia is associated with impaired cognition, especially cognition in social contexts. The... more Schizophrenia is associated with impaired cognition, especially cognition in social contexts. The mirror neuron system (MNS) serves as an important neuronal basis for social cognitive skills; however, previous investigations on the integrity of MNS function in schizophrenia remain approximate. We employed a repetition suppression paradigm that allows for measuring neuronal responses to gesture observation and gesture execution. Cross-modal repetition suppression, i.e., adaptation between observe/execute and execute/observe conditions, was defined as the decisive experimental condition characterizing the unique sensori-motor properties of mirror neurons. Event-related potentials (ERPs) were assessed in 15 schizophrenia patients and 15 matched controls. We isolated an ERP signature of specific adaptation effects to identical hand gestures. Of critical importance, this ERP signature indicated intact intra-modal adaptive pattern, i.e., observe/observe and execute/execute, of comparable magnitude between groups, but deficient cross-modal adaptation, i.e., observe/execute and execute/observe, in schizophrenia patients. Our data provide robust evidence that pure perception and execution of hand gestures are relatively intact in schizophrenia. In contrast, visuo-motor transformation processes mediated by the MNS seem to be specifically disturbed in schizophrenia. These results unambiguously demonstrate MNS deficits in schizophrenia and extend our understanding of the neuronal bases of social dysfunction in this disorder.
![Research paper thumbnail of [Neurocognition, psychosocial outcome and vocational integration]](https://attachments.academia-assets.com/39606417/thumbnails/1.jpg)
](Psychiatrische Praxis, 2004
A lot of progress has been made in the treatment of schizophrenia against hallucinations and delu... more A lot of progress has been made in the treatment of schizophrenia against hallucinations and delusions. However, Schizophrenia still remains a highly disabling disease causing tremendous deficits in social- and vocational functioning. Cognitive deficits are known since the early 90's as a further core feature of schizophrenia, and it has been shown that social- and vocational dysfunctions are closely related to neurocognitive deficits. Whether those findings bear a potential for therapeutic implications still needs to be shown. In this overview therapeutic interventions with respect to cognitive deficits and their effectiveness and their role for vocational rehabilitation will be summarized.
![Research paper thumbnail of [New strategies in schizophrenia: impact of endophentotypes]](https://attachments.academia-assets.com/39606413/thumbnails/1.jpg)
](Psychiatrische Praxis, 2004
Despite the compelling evidence for a strong heritability of schizophrenia, the aetiology and gen... more Despite the compelling evidence for a strong heritability of schizophrenia, the aetiology and genetic underpinnings of this disabling disease still remain unclear. Reasonable explanations for current problems in identifying candidate genes for schizophrenia are the complexity of its genetic background as well as the heterogeneity of the clinical appearance of this disease. For a higher efficiency in genetic investigations, a new approach came up which defines clinically distinct traits much more precisely: the so called endophenotype concept. Schizophrenic patients suffer from marked cognitive deficits. These deficits are closely related to the neurobiological basis of the disease, exhibit a high negative impact on clinical outcome, and may serve as endophenotypes for genetic studies. Identification of neurocognitive endopenotypes is usually performed in terms of a combination of neuropsychological tests and neurophysiological measurements. Thus, future genetic investigations as wel...
Leukemia, 2004
Several studies involving identical twins with concordant leukemia and retrospective scrutiny of ... more Several studies involving identical twins with concordant leukemia and retrospective scrutiny of archived neonatal blood spots have shown that the TEL-AML1 fusion gene in childhood acute lymphoblastic leukemia (ALL) frequently arises before birth. A prenatal origin of childhood leukemia was further supported by the detection of clonotypic immunoglobulin gene rearrangements on neonatal blood spots of children with various other subtypes of ALL. However, no comprehensive study is available linking these clonotypic events. We describe a pair of 5-year-old monozygotic twins with concordant TEL-AML1-positive ALL. Separate leukemic clones were identified in the diagnostic samples since distinct IGH and IGK-Kde gene rearrangements could be detected. Additional differences characterizing the leukemic clones included an aberration of the second, nonrearranged TEL allele observed in one twin only. Interestingly, both the identical TEL-AML1 fusion sequence and distinct immunoglobulin gene rear...
Clinical pharmacology and therapeutics, 1999
The flavin-containing monooxygenase 3 (FMO3) has been shown to be genetically polymorphic. In vit... more The flavin-containing monooxygenase 3 (FMO3) has been shown to be genetically polymorphic. In vitro, the enzyme contributes to the N-oxidation of clozapine, caffeine, and several other drugs. We therefore wanted to analyze population frequencies and allelic linkage of FMO3 mutations and their functional effect on the metabolism of clozapine and caffeine. This study included 204 patients treated with clozapine for schizophrenia and 192 healthy volunteers receiving a 100 mg oral test dose of caffeine. FMO3 polymorphisms M66I, P153L, E158K, V257M, E305X, E308G, and R492W were analyzed by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis. Ratios of serum clozapine N-oxide over clozapine and of urine theobromine versus paraxanthine were used as in vivo indicators of FMO3 activity. From the known FMO3 amino acid variants, only K158 (frequency 0.426), G308 (0.225), and M257 (0.069) were found; mutations I66, L153, X305, and W492 were not found in ...
The Attention Network Test (ANT) provides measures for three different components of visual atten... more The Attention Network Test (ANT) provides measures for three different components of visual attention: executive control (=conflict inhibition), orienting, and alerting. There is reasonable evidence that alterations of attention-mainly in the executive/conflict domain-are associated with susceptibility to psychiatric illness. Specific impairments may be a characteristic for a medical condition such as schizophrenia and thus shift our understanding from a neuropsychological endophenotype to a more precise genetic understanding of this disorder. Study subjects comprised 35 schizophrenic patients and 35 healthy controls (13 female and 22 male in both groups). The ANT was administered to all participants and rated individual responses for the three factors (alerting, orienting, and conflict) and their respective ratios relative to mean reaction times. With regard to gender differences, group comparisons were performed for schizophrenic patients vs. healthy controls. Significant differences between patients and controls could be detected for mean reaction time (639 vs. 538 ms) and for conflict ratio (0.158 vs. 0.191). The latter difference mainly resulted from gender-specific variances of the conflict network in opposite directions. The executive function as represented by the conflict network of visual attention of the ANT is affected in schizophrenia. We have detected hitherto unreported gender-specific differences between healthy controls and schizophrenic patients. Especially as regards the conflict network, the ANT offers a promising methodology to detect a neuropsychological endophenotype of schizophrenia.
DMW - Deutsche Medizinische Wochenschrift, 2005
ABSTRACT
Nature Communications, 2014
Clozapine is a particularly effective antipsychotic medication but its use is curtailed by the ri... more Clozapine is a particularly effective antipsychotic medication but its use is curtailed by the risk of clozapine-induced agranulocytosis/granulocytopenia (CIAG), a severe adverse drug reaction occurring in up to 1% of treated individuals. Identifying genetic risk factors for CIAG could enable safer and more widespread use of clozapine. Here we perform the largest and most comprehensive genetic study of CIAG to date by interrogating 163 cases using genome-wide genotyping and whole-exome sequencing. We find that two loci in the major histocompatibility complex are independently associated with CIAG: a single amino acid in HLA-DQB1 (126Q) (P=4.7 × 10(-14), odds ratio (OR)=0.19, 95% confidence interval (CI)=0.12-0.29) and an amino acid change in the extracellular binding pocket of HLA-B (158T) (P=6.4 × 10(-10), OR=3.3, 95% CI=2.3-4.9). These associations dovetail with the roles of these genes in immunogenetic phenotypes and adverse drug responses for other medications, and provide insight into the pathophysiology of CIAG.
Schizophrenia Research, 2011
Background: The Attention Network Test (ANT) is a well established behavioral measure in neuropsy... more Background: The Attention Network Test (ANT) is a well established behavioral measure in neuropsychological research to assess three different facets of selective attention, i.e., alerting, orienting, and conflict processing. Although the ANT has been applied in healthy individuals and various clinical populations, data on retest reliability are scarce in healthy samples and lacking for clinical populations. The objective of the present study was a longitudinal assessment of relevant ANT network measures in healthy controls and schizophrenic patients. Methods: Forty-five schizophrenic patients and 55 healthy controls were tested with ANT in a test-retest design with an average interval of 7.4 months between test sessions. Test-retest reliability was analyzed with Pearson and Intra-class correlations. Results: Healthy controls revealed moderate to high test-retest correlations for mean reaction time, mean accuracy, conflict effect, and conflict error rates. In schizophrenic patients, moderate test-retest correlations for mean reaction time, orienting effect, and conflict effect were found. The analysis of error rates in schizophrenic patients revealed very low test-retest correlations. Conclusions: The current study provides converging statistical evidence that the conflict effect and mean reaction time of ANT yield acceptable test-retest reliabilities in healthy controls and, investigated longitudinally for the first time, also in schizophrenia. Obtained differences of alerting and orienting effects in schizophrenia case-control studies should be considered more carefully. The analysis of error rates revealed heterogeneous results and therefore is not recommended for case control studies in schizophrenia.
Schizophrenia Research, 2010
Background: In a previous study, we found a reduced amplitude modulation of the visual P3 compone... more Background: In a previous study, we found a reduced amplitude modulation of the visual P3 component of the event-related potential (ERP) in schizophrenic patients compared with healthy controls during inhibition in the Attention Network Test (ANT). The objective of the present study was to replicate this finding and to explore whether this cortical processing deficit is specific to schizophrenia. Methods: Sixteen schizophrenic patients, sixteen depressive patients, and sixteen healthy controls matched for age, sex, and education were included. Participants were tested with the ANT, a test of selective attention that provides behavioral estimates for alerting, orienting, and inhibition. 32-Channel electroencephalogram was recorded and visual P3 amplitudes were topographically analyzed and compared between groups. Results: There were no significant behavioral between-group differences in terms of mean reaction time, accuracy, and ANT effects alerting, orienting, and inhibition. Absolute visual P3 amplitude was not reduced in schizophrenia or depression. P3 amplitude modulation was defined as P3 amplitude at Pz as a function of ANT flanker conditions. We found a parietal P3 amplitude modulation deficit in schizophrenic patients (−.015) that was absent in both healthy controls (−.705; p = .002) and depressive patients (− 1.022; p = .001). Conclusion: The results provide evidence that a deficit of visual P3 amplitude modulation distinguishes schizophrenia from healthy and disease controls and provides greater discriminative power than absolute visual P3 amplitude.
Schizophrenia Bulletin, 2008
Background: Executive control of attention in schizophrenia has recently been assessed by means o... more Background: Executive control of attention in schizophrenia has recently been assessed by means of the Attention Network Test (ANT). In the past, for tasks assessing executive attention, findings in schizophrenia have been contradictory, among others suggesting a lack of increased stimulus interference effects. Attention and executive functioning are substantially influenced by candidate genes of schizophrenia, including the functional single-nucleotide polymorphism catechol-o-methyltransferase (COMT) Val 108/158 Met, with task-dependent, specific effects of Met allele load on cognitive function. Therefore, we aimed at investigating executive attention in schizophrenic patients (SZP) as compared with healthy controls (HC), and to assess the specific impact of COMT Val 108/158 Met on executive attention, using ANT. Methods: We applied ANT to 63 SZP and 40 HC. We calculated a general linear model to investigate the influence of affection status and the COMT Val 108/158 Met genotype on executive attention as assessed by the ANT. Results: Multivariate analysis of variance revealed a significant effect of group on executive attention. SZP exhibited smaller conflict effects in the ANT. Met allele load significantly modulated executive attention efficiency, with homozygous Met individuals showing low overall reaction time but increased effects conflicting stimulus information in executive attention. Conclusions: Our data suggest a disease-related dissociation of executive attention with reduced conflict effects in SZP. Furthermore, they support the hypothesis of differential tonic-phasic dopamine activation and specific dopamine level effects in different cognitive tasks, which helps interpreting contradictory findings of Met allele load on cognitive performance. Disease status seems to modulate the impact of COMT Val 108/158 Met on cognitive performance.
Schizophrenia Bulletin, 2013
Attention deficits, among other cognitive deficits, are frequently observed in schizophrenia. Alt... more Attention deficits, among other cognitive deficits, are frequently observed in schizophrenia. Although valid and reliable neurocognitive tasks have been established to assess attention deficits in schizophrenia, the hierarchical value of those tests as diagnostic discriminants on a single-subject level remains unclear. Thus, much research is devoted to attention deficits that are unlikely to be translated into clinical practice. On the other hand, a clear hierarchy of attention deficits in schizophrenia could considerably aid diagnostic decisions and may prove beneficial for longitudinal monitoring of therapeutic advances. To propose a diagnostic hierarchy of attention deficits in schizophrenia, we investigated several facets of attention in 86 schizophrenia patients and 86 healthy controls using a set of established attention tests. We applied state-of-the-art machine learning algorithms to determine attentive test variables that enable an automated differentiation between schizophrenia patients and healthy controls. After feature preranking, hypothesis building, and hypothesis validation, the polynomial support vector machine classifier achieved a classification accuracy of 90.70% ± 2.9% using psychomotor speed and 3 different attention parameters derived from sustained and divided attention tasks. Our study proposes, to the best of our knowledge, the first hierarchy of attention deficits in schizophrenia by identifying the most discriminative attention parameters among a variety of attention deficits found in schizophrenia patients. Our results offer a starting point for hierarchy building of schizophreniaassociated attention deficits and contribute to translating these concepts into diagnostic and therapeutic practice on a single-subject level.
Psychopharmacology, 2000
Clozapine is a unique antipsychotic drug, outstanding for its lack of extrapyramidal side-effects... more Clozapine is a unique antipsychotic drug, outstanding for its lack of extrapyramidal side-effects and its superior efficacy in refractory schizophrenia. However, an unambiguous concentration-response relationship has not yet been established. We investigated serum concentrations of clozapine, norclozapine and clozapine-N-oxide in psychiatric in- and outpatients to identify particular metabolic patterns in clozapine responders and non-responders and putative threshold levels for clozapine response. Psychiatric assessments, CYP2D6 genotype, and weekly serum concentrations of clozapine, norclozapine and clozapine-N-oxide were obtained in 34 adult schizophrenic in-and outpatients (18 men, 16 women) during 10 weeks of clozapine treatment with a naturalistic dose design. Responders (n=21) displayed significantly lower serum concentrations of clozapine corrected for dose compared to non-responders (n=13; P<0.05), while none of the other parameters (absolute clozapine concentration, metabolite ratios, gender) were different. Smokers had significantly lower dose-corrected clozapine concentrations. A positive correlation was observed between age and average steady state clozapine concentrations. These findings indicate a possible link between CYP activity and response to clozapine that is not mediated through differences in serum concentrations. No clinically meaningful pattern in serum parameters could be identified that differentiates responders from non-responders. Thus, clozapine TDM seems ineffective for predicting clinical response. Smoking behavior is a major determinant of clozapine clearance while CYP2D6 genotype does not impact clozapine disposition.
Psychiatry Research, 2009
The Attention Network Test (ANT) provides measures for three different components of visual atten... more The Attention Network Test (ANT) provides measures for three different components of visual attention: executive control (=conflict inhibition), orienting, and alerting. There is reasonable evidence that alterations of attention-mainly in the executive/conflict domain-are associated with susceptibility to psychiatric illness. Specific impairments may be a characteristic for a medical condition such as schizophrenia and thus shift our understanding from a neuropsychological endophenotype to a more precise genetic understanding of this disorder. Study subjects comprised 35 schizophrenic patients and 35 healthy controls (13 female and 22 male in both groups). The ANT was administered to all participants and rated individual responses for the three factors (alerting, orienting, and conflict) and their respective ratios relative to mean reaction times. With regard to gender differences, group comparisons were performed for schizophrenic patients vs. healthy controls. Significant differences between patients and controls could be detected for mean reaction time (639 vs. 538 ms) and for conflict ratio (0.158 vs. 0.191). The latter difference mainly resulted from gender-specific variances of the conflict network in opposite directions. The executive function as represented by the conflict network of visual attention of the ANT is affected in schizophrenia. We have detected hitherto unreported gender-specific differences between healthy controls and schizophrenic patients. Especially as regards the conflict network, the ANT offers a promising methodology to detect a neuropsychological endophenotype of schizophrenia.
PLoS ONE, 2014
Background: The Continuous Performance Test-Identical Pairs version (CPT-IP) is a well-establishe... more Background: The Continuous Performance Test-Identical Pairs version (CPT-IP) is a well-established measure of sustained attention, and its more challenging versions are particularly suited to detect subtle processing deficits in patients with schizophrenia. However, while there are few longitudinal samples for the CPT-IP, no study has addressed stability for more than two month in patients with schizophrenia. Assessing long-term test-retest reliability of the CPT-IP would facilitate the ability of clinicians to draw conclusions from studies involving interventions as long term cognitive or pharmacological treatments. The present study assessed 12 month test-retest reliability for the two most challenging versions of CPT-IP (4digit and shapes) in a matched sample of clinically stable schizophrenia outpatients and healthy controls.
Pharmacopsychiatry, 1999
Mu"-. 2, Whether or not olanzapine causes bone marrow toxicity is still a matter of debate. In sp... more Mu"-. 2, Whether or not olanzapine causes bone marrow toxicity is still a matter of debate. In spite of pre-marketing and post-marketing clinical trials, and although there have been no cases in animals of olanzapine-induced neutropenia or agranulocytosis, the risk of bone marrow toxicity cannot be excluded. The present paper addresses the following questions: what is the potential background of drug-induced agranulocytosis? Are there any case reports supporting the view that olanzapine has relevant bone marrow toxicity? What strategies might be helpful in identifying the pathological mechanisms underlying this side effect? Downloaded by: Medizinische Bibliothek. Copyrighted material. Liebemon]A. Yunis], Egea E, Canoso RXKaneJM. Yunis El: HLA-B38. DR4. DQOw3 and clozapine-induced agranulocytosis in Jewish patients with schizophrenia. Arch. Gen. Psychiatry 1990: 47: 945 -948 NemeroJJ CB: Dosing the antipsychotic olanzapine. J. Clin.
Pharmacopsychiatry, 2000
The pathomechanisms of most drug-induced agranulocytoses are unclear; however, there are some stu... more The pathomechanisms of most drug-induced agranulocytoses are unclear; however, there are some studies pointing to genetic determinants. Some drug-induced agranulocytoses such as clozapine-induced agranulocytosis (CA) may be regarded as an idiosyncratic drug reaction because of its preclinical and clinical characteristics. To study some aspects of the genetic background of CA further, polymorphisms of specific metabolizing enzyme systems of clozapine were examined. Thirty-one schizophrenic patients with CA and 77 schizophrenic comparison subjects without this adverse effect underwent genotyping of a recently discovered G(-463)A polymorphism of myeloperoxidase (MPO) gene and cytochrome P4502D6. Neither the MPO mutation nor specific genotypes of cytochrome P4502D6 were associated with CA. Both were equally distributed among CA patients and controls. Thus, our data suggest lack of evidence of an association of CA and genetically variable activity of these specific drug metabolizing enzymes; however, this may be due to statistical reasons only. Thus, further studies with greater CA samples are necessary to draw final conclusions about these genetically based hypotheses.
European Psychiatry, 2014
Key points • Schizophrenia is an umbrella term for a group of disorders that present with a commo... more Key points • Schizophrenia is an umbrella term for a group of disorders that present with a common set of symptoms; subtypes are diverse and reflect varied prognoses and treatment responses. • ICD 10 and the DSM IV are the current diagnostic schedules used for diagnosing schizophrenia. DSM V is in final stages of revision and is likely to be published in the fall of 2013. ICD is also being revised, and ICD 11 is likely to be published in 2014. • Development of schizophrenia is governed by a multifactorial model that includes genetic, neurodevelopmental, social, and psychological triggers. • Whether atypical antipsychotics (new generation) are superior to typical ones (old generation) in regard to efficacy and side-effect profiles continues to be debated. • Schizophrenia is more than an illness that affects individuals; it affects families and, at times, communities. Historical note and nomenclature Historically, schizophrenia can be traced back to old Pharaonic Egypt as far as the s...
Schizophrenia Research, 2015
Schizophrenia is associated with impaired cognition, especially cognition in social contexts. The... more Schizophrenia is associated with impaired cognition, especially cognition in social contexts. The mirror neuron system (MNS) serves as an important neuronal basis for social cognitive skills; however, previous investigations on the integrity of MNS function in schizophrenia remain approximate. We employed a repetition suppression paradigm that allows for measuring neuronal responses to gesture observation and gesture execution. Cross-modal repetition suppression, i.e., adaptation between observe/execute and execute/observe conditions, was defined as the decisive experimental condition characterizing the unique sensori-motor properties of mirror neurons. Event-related potentials (ERPs) were assessed in 15 schizophrenia patients and 15 matched controls. We isolated an ERP signature of specific adaptation effects to identical hand gestures. Of critical importance, this ERP signature indicated intact intra-modal adaptive pattern, i.e., observe/observe and execute/execute, of comparable magnitude between groups, but deficient cross-modal adaptation, i.e., observe/execute and execute/observe, in schizophrenia patients. Our data provide robust evidence that pure perception and execution of hand gestures are relatively intact in schizophrenia. In contrast, visuo-motor transformation processes mediated by the MNS seem to be specifically disturbed in schizophrenia. These results unambiguously demonstrate MNS deficits in schizophrenia and extend our understanding of the neuronal bases of social dysfunction in this disorder.
Psychiatrische Praxis, 2004
A lot of progress has been made in the treatment of schizophrenia against hallucinations and delu... more A lot of progress has been made in the treatment of schizophrenia against hallucinations and delusions. However, Schizophrenia still remains a highly disabling disease causing tremendous deficits in social- and vocational functioning. Cognitive deficits are known since the early 90's as a further core feature of schizophrenia, and it has been shown that social- and vocational dysfunctions are closely related to neurocognitive deficits. Whether those findings bear a potential for therapeutic implications still needs to be shown. In this overview therapeutic interventions with respect to cognitive deficits and their effectiveness and their role for vocational rehabilitation will be summarized.
Psychiatrische Praxis, 2004
Despite the compelling evidence for a strong heritability of schizophrenia, the aetiology and gen... more Despite the compelling evidence for a strong heritability of schizophrenia, the aetiology and genetic underpinnings of this disabling disease still remain unclear. Reasonable explanations for current problems in identifying candidate genes for schizophrenia are the complexity of its genetic background as well as the heterogeneity of the clinical appearance of this disease. For a higher efficiency in genetic investigations, a new approach came up which defines clinically distinct traits much more precisely: the so called endophenotype concept. Schizophrenic patients suffer from marked cognitive deficits. These deficits are closely related to the neurobiological basis of the disease, exhibit a high negative impact on clinical outcome, and may serve as endophenotypes for genetic studies. Identification of neurocognitive endopenotypes is usually performed in terms of a combination of neuropsychological tests and neurophysiological measurements. Thus, future genetic investigations as wel...
Leukemia, 2004
Several studies involving identical twins with concordant leukemia and retrospective scrutiny of ... more Several studies involving identical twins with concordant leukemia and retrospective scrutiny of archived neonatal blood spots have shown that the TEL-AML1 fusion gene in childhood acute lymphoblastic leukemia (ALL) frequently arises before birth. A prenatal origin of childhood leukemia was further supported by the detection of clonotypic immunoglobulin gene rearrangements on neonatal blood spots of children with various other subtypes of ALL. However, no comprehensive study is available linking these clonotypic events. We describe a pair of 5-year-old monozygotic twins with concordant TEL-AML1-positive ALL. Separate leukemic clones were identified in the diagnostic samples since distinct IGH and IGK-Kde gene rearrangements could be detected. Additional differences characterizing the leukemic clones included an aberration of the second, nonrearranged TEL allele observed in one twin only. Interestingly, both the identical TEL-AML1 fusion sequence and distinct immunoglobulin gene rear...
Clinical pharmacology and therapeutics, 1999
The flavin-containing monooxygenase 3 (FMO3) has been shown to be genetically polymorphic. In vit... more The flavin-containing monooxygenase 3 (FMO3) has been shown to be genetically polymorphic. In vitro, the enzyme contributes to the N-oxidation of clozapine, caffeine, and several other drugs. We therefore wanted to analyze population frequencies and allelic linkage of FMO3 mutations and their functional effect on the metabolism of clozapine and caffeine. This study included 204 patients treated with clozapine for schizophrenia and 192 healthy volunteers receiving a 100 mg oral test dose of caffeine. FMO3 polymorphisms M66I, P153L, E158K, V257M, E305X, E308G, and R492W were analyzed by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis. Ratios of serum clozapine N-oxide over clozapine and of urine theobromine versus paraxanthine were used as in vivo indicators of FMO3 activity. From the known FMO3 amino acid variants, only K158 (frequency 0.426), G308 (0.225), and M257 (0.069) were found; mutations I66, L153, X305, and W492 were not found in ...
The Attention Network Test (ANT) provides measures for three different components of visual atten... more The Attention Network Test (ANT) provides measures for three different components of visual attention: executive control (=conflict inhibition), orienting, and alerting. There is reasonable evidence that alterations of attention-mainly in the executive/conflict domain-are associated with susceptibility to psychiatric illness. Specific impairments may be a characteristic for a medical condition such as schizophrenia and thus shift our understanding from a neuropsychological endophenotype to a more precise genetic understanding of this disorder. Study subjects comprised 35 schizophrenic patients and 35 healthy controls (13 female and 22 male in both groups). The ANT was administered to all participants and rated individual responses for the three factors (alerting, orienting, and conflict) and their respective ratios relative to mean reaction times. With regard to gender differences, group comparisons were performed for schizophrenic patients vs. healthy controls. Significant differences between patients and controls could be detected for mean reaction time (639 vs. 538 ms) and for conflict ratio (0.158 vs. 0.191). The latter difference mainly resulted from gender-specific variances of the conflict network in opposite directions. The executive function as represented by the conflict network of visual attention of the ANT is affected in schizophrenia. We have detected hitherto unreported gender-specific differences between healthy controls and schizophrenic patients. Especially as regards the conflict network, the ANT offers a promising methodology to detect a neuropsychological endophenotype of schizophrenia.
DMW - Deutsche Medizinische Wochenschrift, 2005
ABSTRACT
Nature Communications, 2014
Clozapine is a particularly effective antipsychotic medication but its use is curtailed by the ri... more Clozapine is a particularly effective antipsychotic medication but its use is curtailed by the risk of clozapine-induced agranulocytosis/granulocytopenia (CIAG), a severe adverse drug reaction occurring in up to 1% of treated individuals. Identifying genetic risk factors for CIAG could enable safer and more widespread use of clozapine. Here we perform the largest and most comprehensive genetic study of CIAG to date by interrogating 163 cases using genome-wide genotyping and whole-exome sequencing. We find that two loci in the major histocompatibility complex are independently associated with CIAG: a single amino acid in HLA-DQB1 (126Q) (P=4.7 × 10(-14), odds ratio (OR)=0.19, 95% confidence interval (CI)=0.12-0.29) and an amino acid change in the extracellular binding pocket of HLA-B (158T) (P=6.4 × 10(-10), OR=3.3, 95% CI=2.3-4.9). These associations dovetail with the roles of these genes in immunogenetic phenotypes and adverse drug responses for other medications, and provide insight into the pathophysiology of CIAG.
Schizophrenia Research, 2011
Background: The Attention Network Test (ANT) is a well established behavioral measure in neuropsy... more Background: The Attention Network Test (ANT) is a well established behavioral measure in neuropsychological research to assess three different facets of selective attention, i.e., alerting, orienting, and conflict processing. Although the ANT has been applied in healthy individuals and various clinical populations, data on retest reliability are scarce in healthy samples and lacking for clinical populations. The objective of the present study was a longitudinal assessment of relevant ANT network measures in healthy controls and schizophrenic patients. Methods: Forty-five schizophrenic patients and 55 healthy controls were tested with ANT in a test-retest design with an average interval of 7.4 months between test sessions. Test-retest reliability was analyzed with Pearson and Intra-class correlations. Results: Healthy controls revealed moderate to high test-retest correlations for mean reaction time, mean accuracy, conflict effect, and conflict error rates. In schizophrenic patients, moderate test-retest correlations for mean reaction time, orienting effect, and conflict effect were found. The analysis of error rates in schizophrenic patients revealed very low test-retest correlations. Conclusions: The current study provides converging statistical evidence that the conflict effect and mean reaction time of ANT yield acceptable test-retest reliabilities in healthy controls and, investigated longitudinally for the first time, also in schizophrenia. Obtained differences of alerting and orienting effects in schizophrenia case-control studies should be considered more carefully. The analysis of error rates revealed heterogeneous results and therefore is not recommended for case control studies in schizophrenia.
Schizophrenia Research, 2010
Background: In a previous study, we found a reduced amplitude modulation of the visual P3 compone... more Background: In a previous study, we found a reduced amplitude modulation of the visual P3 component of the event-related potential (ERP) in schizophrenic patients compared with healthy controls during inhibition in the Attention Network Test (ANT). The objective of the present study was to replicate this finding and to explore whether this cortical processing deficit is specific to schizophrenia. Methods: Sixteen schizophrenic patients, sixteen depressive patients, and sixteen healthy controls matched for age, sex, and education were included. Participants were tested with the ANT, a test of selective attention that provides behavioral estimates for alerting, orienting, and inhibition. 32-Channel electroencephalogram was recorded and visual P3 amplitudes were topographically analyzed and compared between groups. Results: There were no significant behavioral between-group differences in terms of mean reaction time, accuracy, and ANT effects alerting, orienting, and inhibition. Absolute visual P3 amplitude was not reduced in schizophrenia or depression. P3 amplitude modulation was defined as P3 amplitude at Pz as a function of ANT flanker conditions. We found a parietal P3 amplitude modulation deficit in schizophrenic patients (−.015) that was absent in both healthy controls (−.705; p = .002) and depressive patients (− 1.022; p = .001). Conclusion: The results provide evidence that a deficit of visual P3 amplitude modulation distinguishes schizophrenia from healthy and disease controls and provides greater discriminative power than absolute visual P3 amplitude.
Schizophrenia Bulletin, 2008
Background: Executive control of attention in schizophrenia has recently been assessed by means o... more Background: Executive control of attention in schizophrenia has recently been assessed by means of the Attention Network Test (ANT). In the past, for tasks assessing executive attention, findings in schizophrenia have been contradictory, among others suggesting a lack of increased stimulus interference effects. Attention and executive functioning are substantially influenced by candidate genes of schizophrenia, including the functional single-nucleotide polymorphism catechol-o-methyltransferase (COMT) Val 108/158 Met, with task-dependent, specific effects of Met allele load on cognitive function. Therefore, we aimed at investigating executive attention in schizophrenic patients (SZP) as compared with healthy controls (HC), and to assess the specific impact of COMT Val 108/158 Met on executive attention, using ANT. Methods: We applied ANT to 63 SZP and 40 HC. We calculated a general linear model to investigate the influence of affection status and the COMT Val 108/158 Met genotype on executive attention as assessed by the ANT. Results: Multivariate analysis of variance revealed a significant effect of group on executive attention. SZP exhibited smaller conflict effects in the ANT. Met allele load significantly modulated executive attention efficiency, with homozygous Met individuals showing low overall reaction time but increased effects conflicting stimulus information in executive attention. Conclusions: Our data suggest a disease-related dissociation of executive attention with reduced conflict effects in SZP. Furthermore, they support the hypothesis of differential tonic-phasic dopamine activation and specific dopamine level effects in different cognitive tasks, which helps interpreting contradictory findings of Met allele load on cognitive performance. Disease status seems to modulate the impact of COMT Val 108/158 Met on cognitive performance.
Schizophrenia Bulletin, 2013
Attention deficits, among other cognitive deficits, are frequently observed in schizophrenia. Alt... more Attention deficits, among other cognitive deficits, are frequently observed in schizophrenia. Although valid and reliable neurocognitive tasks have been established to assess attention deficits in schizophrenia, the hierarchical value of those tests as diagnostic discriminants on a single-subject level remains unclear. Thus, much research is devoted to attention deficits that are unlikely to be translated into clinical practice. On the other hand, a clear hierarchy of attention deficits in schizophrenia could considerably aid diagnostic decisions and may prove beneficial for longitudinal monitoring of therapeutic advances. To propose a diagnostic hierarchy of attention deficits in schizophrenia, we investigated several facets of attention in 86 schizophrenia patients and 86 healthy controls using a set of established attention tests. We applied state-of-the-art machine learning algorithms to determine attentive test variables that enable an automated differentiation between schizophrenia patients and healthy controls. After feature preranking, hypothesis building, and hypothesis validation, the polynomial support vector machine classifier achieved a classification accuracy of 90.70% ± 2.9% using psychomotor speed and 3 different attention parameters derived from sustained and divided attention tasks. Our study proposes, to the best of our knowledge, the first hierarchy of attention deficits in schizophrenia by identifying the most discriminative attention parameters among a variety of attention deficits found in schizophrenia patients. Our results offer a starting point for hierarchy building of schizophreniaassociated attention deficits and contribute to translating these concepts into diagnostic and therapeutic practice on a single-subject level.
Psychopharmacology, 2000
Clozapine is a unique antipsychotic drug, outstanding for its lack of extrapyramidal side-effects... more Clozapine is a unique antipsychotic drug, outstanding for its lack of extrapyramidal side-effects and its superior efficacy in refractory schizophrenia. However, an unambiguous concentration-response relationship has not yet been established. We investigated serum concentrations of clozapine, norclozapine and clozapine-N-oxide in psychiatric in- and outpatients to identify particular metabolic patterns in clozapine responders and non-responders and putative threshold levels for clozapine response. Psychiatric assessments, CYP2D6 genotype, and weekly serum concentrations of clozapine, norclozapine and clozapine-N-oxide were obtained in 34 adult schizophrenic in-and outpatients (18 men, 16 women) during 10 weeks of clozapine treatment with a naturalistic dose design. Responders (n=21) displayed significantly lower serum concentrations of clozapine corrected for dose compared to non-responders (n=13; P<0.05), while none of the other parameters (absolute clozapine concentration, metabolite ratios, gender) were different. Smokers had significantly lower dose-corrected clozapine concentrations. A positive correlation was observed between age and average steady state clozapine concentrations. These findings indicate a possible link between CYP activity and response to clozapine that is not mediated through differences in serum concentrations. No clinically meaningful pattern in serum parameters could be identified that differentiates responders from non-responders. Thus, clozapine TDM seems ineffective for predicting clinical response. Smoking behavior is a major determinant of clozapine clearance while CYP2D6 genotype does not impact clozapine disposition.
Psychiatry Research, 2009
The Attention Network Test (ANT) provides measures for three different components of visual atten... more The Attention Network Test (ANT) provides measures for three different components of visual attention: executive control (=conflict inhibition), orienting, and alerting. There is reasonable evidence that alterations of attention-mainly in the executive/conflict domain-are associated with susceptibility to psychiatric illness. Specific impairments may be a characteristic for a medical condition such as schizophrenia and thus shift our understanding from a neuropsychological endophenotype to a more precise genetic understanding of this disorder. Study subjects comprised 35 schizophrenic patients and 35 healthy controls (13 female and 22 male in both groups). The ANT was administered to all participants and rated individual responses for the three factors (alerting, orienting, and conflict) and their respective ratios relative to mean reaction times. With regard to gender differences, group comparisons were performed for schizophrenic patients vs. healthy controls. Significant differences between patients and controls could be detected for mean reaction time (639 vs. 538 ms) and for conflict ratio (0.158 vs. 0.191). The latter difference mainly resulted from gender-specific variances of the conflict network in opposite directions. The executive function as represented by the conflict network of visual attention of the ANT is affected in schizophrenia. We have detected hitherto unreported gender-specific differences between healthy controls and schizophrenic patients. Especially as regards the conflict network, the ANT offers a promising methodology to detect a neuropsychological endophenotype of schizophrenia.
PLoS ONE, 2014
Background: The Continuous Performance Test-Identical Pairs version (CPT-IP) is a well-establishe... more Background: The Continuous Performance Test-Identical Pairs version (CPT-IP) is a well-established measure of sustained attention, and its more challenging versions are particularly suited to detect subtle processing deficits in patients with schizophrenia. However, while there are few longitudinal samples for the CPT-IP, no study has addressed stability for more than two month in patients with schizophrenia. Assessing long-term test-retest reliability of the CPT-IP would facilitate the ability of clinicians to draw conclusions from studies involving interventions as long term cognitive or pharmacological treatments. The present study assessed 12 month test-retest reliability for the two most challenging versions of CPT-IP (4digit and shapes) in a matched sample of clinically stable schizophrenia outpatients and healthy controls.
Pharmacopsychiatry, 1999
Mu"-. 2, Whether or not olanzapine causes bone marrow toxicity is still a matter of debate. In sp... more Mu"-. 2, Whether or not olanzapine causes bone marrow toxicity is still a matter of debate. In spite of pre-marketing and post-marketing clinical trials, and although there have been no cases in animals of olanzapine-induced neutropenia or agranulocytosis, the risk of bone marrow toxicity cannot be excluded. The present paper addresses the following questions: what is the potential background of drug-induced agranulocytosis? Are there any case reports supporting the view that olanzapine has relevant bone marrow toxicity? What strategies might be helpful in identifying the pathological mechanisms underlying this side effect? Downloaded by: Medizinische Bibliothek. Copyrighted material. Liebemon]A. Yunis], Egea E, Canoso RXKaneJM. Yunis El: HLA-B38. DR4. DQOw3 and clozapine-induced agranulocytosis in Jewish patients with schizophrenia. Arch. Gen. Psychiatry 1990: 47: 945 -948 NemeroJJ CB: Dosing the antipsychotic olanzapine. J. Clin.
Pharmacopsychiatry, 2000
The pathomechanisms of most drug-induced agranulocytoses are unclear; however, there are some stu... more The pathomechanisms of most drug-induced agranulocytoses are unclear; however, there are some studies pointing to genetic determinants. Some drug-induced agranulocytoses such as clozapine-induced agranulocytosis (CA) may be regarded as an idiosyncratic drug reaction because of its preclinical and clinical characteristics. To study some aspects of the genetic background of CA further, polymorphisms of specific metabolizing enzyme systems of clozapine were examined. Thirty-one schizophrenic patients with CA and 77 schizophrenic comparison subjects without this adverse effect underwent genotyping of a recently discovered G(-463)A polymorphism of myeloperoxidase (MPO) gene and cytochrome P4502D6. Neither the MPO mutation nor specific genotypes of cytochrome P4502D6 were associated with CA. Both were equally distributed among CA patients and controls. Thus, our data suggest lack of evidence of an association of CA and genetically variable activity of these specific drug metabolizing enzymes; however, this may be due to statistical reasons only. Thus, further studies with greater CA samples are necessary to draw final conclusions about these genetically based hypotheses.