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STRUCTURAL AND NEUROFUNCTIONAL ABNORMALITIES IN THE AT-RISK MENTAL STATE (ARMS) OF PSYCHOSIS
112
Abstracts
disease phases from both the neurobiological and behavioral perspectives. In this context, imaging studies revealed that crosssectional and longitudinal abnormalities exist on the structural and functional brain dimensions of at-risk individuals and firstepisode patients. These findings have offered important insights into the brain pathology emerging during the transition from the prodromal state to the full-blown clinical picture of schizophrenia. Thus, the accumulating brain alterations described by recent neuroimaging studies may be interpreted within the concept of a late neurodevelopmental process that evolves when higher-order cortical areas are placed “under functional demand” during the critical transition from adolescence to adulthood. Beside these advances in the basic science of psychosis, the recent advent of multivariate pattern recognition techniques in the neuroimaging field has opened up new possibilities to derive valid biomarkers from, up to now, group-level statistical inferences that may allow for the individualized early recognition of the at-risk mental state and the prediction of disease transition. Thus, these findings may stir up the debate whether (a) structural and/or functional brain abnormalities represent reliable intermediate phenotypes, or “endophenotypes” of psychosis and whether (b) these imagingbased endophenotypes are sufficiently sensitive and specific markers of the underlying neurobiology and its behavioral expressions. A positive answer to these questions would allow neuroimaging techniques to cross the bridge between basic science and its potential clinical applications. The symposium aims to bring together leading experts from the field to present the state-of-the-art basic science aspects of neuroimaging research as well as its clinical perspectives regarding the application of individualized neurodiagnostic procedures for the early recognition of the high-risk states and the early phases of psychosis as well as the prediction of disease transition. References: Gur RE, Keshavan MS, Lawrie SM. Deconstructing psychosis with human brain imaging. Schizophr Bull. 2007 Jul;33 (4):921-31Sun D, van Erp TG, Thompson PM, Bearden CE, Daley M, Kushan L, Hardt ME, Nuechterlein KH, Toga AW, Cannon TD. Elucidating a Magnetic Resonance Imaging-Based Neuroanatomic Biomarker for Psychosis: Classification Analysis Using Probabilistic Brain Atlas and Machine Learning Algorithms. Biol Psychiatry. 2009; in press. Borgwardt SJ, Riecher-Rössler A, Dazzan P, Chitnis X, Aston J, Drewe M, Gschwandtner U, Haller S, Pflüger M, Rechsteiner E, Semenin V, Stieglitz RD, Radü EW, McGuire PK. Regional grey matter abnormalities in the At Risk Mental State. Biological Psychiatry.2007;15(61):1148-56.Koutsouleris N, Meisenzahl EM, Davatzikos C, Bottlender R, Frodl T, Scheuerecker J, Schmitt G, Zetzsche T, Decker P, Reiser M, Möller HJ, Gaser C. Use of neuroanatomical pattern classification to identify subjects in atrisk mental states of psychosis and predict disease transition. Arch Gen Psychiatry. 2009;66(7):700-12.
notypes are genetically mediated but are not on the causal pathways to psychosis (i.e., intermediate phenotypes), (b) other endophenotypes are not necessarily genetic but may still be intermediate phenotypes and (c) existing technologies can actually distinguish between schizophrenia and bipolar disorder, and between the relatives of patients with these disorders. I will conclude that endophenotypes are a useful concept in psychosis research, particularly in terms of helping to specify mechanisms but that researchers need to be careful about the use of these terms and the implications of these uses.
doi:10.1016/j.schres.2010.02.032
PROGRESSIVE BRAIN CHANGES ACROSS THE TRANSITION TO PSYCHOSIS: WHERE TO FROM HERE? Stephen Wood Melbourne Neuropsychiatry Centre, University of Melbourne and Melbourne Health Melbourne, Victoria, Australia Although the underlying neurobiology of emerging psychotic disorders is not well understood, there is a growing conviction that there are progressive brain changes in patients at clinical high risk for the illness. These changes are likely to begin well before the frank onset of the disorder and may continue for a number of years. In this talk, I will summarize the extant neuroimaging studies of people at clinical high risk for psychosis, both cross-sectional and longitudinal. By and large, there are few definitive markers that distinguish those who go on to develop the illness from those who do not. The two most consistently abnormal brain regions in schizophrenia research, the hippocampi and the lateral ventricles, do not show volumes significantly different to those of healthy controls prior to psychosis onset. However, frontal lobe measures (eg, cortical thickness in the anterior cingulate) do show promise, as do functional imaging measures sensitive to prefrontal cortex dysfunction. Further, longitudinal magnetic resonance imaging findings in individuals at clinical high risk show that there are excessive neuroanatomical changes in those who convert to psychosis. These aberrant changes are observed most prominently in medial temporal and prefrontal cortical regions. While the pathological processes underlying such changes remain unclear, speculatively they may reflect anomalies in genetic and/or other endogenous mechanisms responsible for brain maturation, the adverse effects of intense or prolonged stress, or other environmental factors. Active changes during transition to illness may present the potential to intervene and ameliorate these changes with potential benefit clinically.
doi:10.1016/j.schres.2010.02.031 doi:10.1016/j.schres.2010.02.033 ARE ENDOPHENOTYPES A USEFUL CONCEPT? Stephen Lawrie University of Edinburgh, Scotland, UK The rise of interest in endophenotypes appears related to frustration with the pace of progress in understanding schizophrenia and related disorders. We tend to think of endophenotypes, following Gottesman, as genetically mediated “hidden phenotypes” which are closely related to genetic risk factors but also raise the risk of clinical “exophenotypes”. In this presentation, I will challenge these views. I will demonstrate that (a) some endophe-
STRUCTURAL AND NEUROFUNCTIONAL ABNORMALITIES IN THE AT-RISK MENTAL STATE (ARMS) OF PSYCHOSIS Stefan Borgwardt University Hospital of Basel, Switzerland Over the past decade there has been an exponential growing of neuroimaging research in the early phases of psychosis. Despite the complexity of techniques worldwide engaged and the number of published papers, the clinical significance of anatomical or functional abnormalities is still mostly unknown. Thus, recent research
Abstracts
has started to longitudinally assess brain structure and function, with the aim to align functional imaging with clinical psychiatry. The aim of the study was to investigate brain structure and function in individuals with an At Risk Mental State (ARMS) relative to patients with first-episode psychosis (FE) and healthy volunteers (HC). The subjects were recruited within the Basel Early Detection of Psychosis Clinic (FEPSY) which has been established at the Psychiatric Outpatient Department, University Hospital Basel. Cross-sectional and longitudinal structural and functional magnetic resonance imaging (MRI) data were acquired using a 3.0 T scanner from individuals with an ARMS, similar to the PACE criteria, FE and HC. Images were processed and analysed using voxel based morphometry (VBM) and region-of-interest methods. Volumetric and neurofunctional abnormalities in areas that are also altered in schizophrenia were associated with specific abnormalities in people with an ARMS. However, results indicate that treatment with typical as well as atypical antipsychotics may also contribute to structural alterations. To conclude, some structural and neurofunctional abnormalities were specific to individuals with an ARMS and may be a correlate of their increased vulnerability to psychosis. Further changes within the ARMS appear to be associated with the subsequent onset of psychosis.
doi:10.1016/j.schres.2010.02.034
MRI-BASED BIOMARKERS FOR INDIVIDUALIZED NEURODIAGNOSTICS IN THE AT-RISK MENTAL STATE AND THE EARLY PHASE OF PSYCHOSIS Nikolaos Koutsouleris Ludwig-Maximilian-University, Munich, Bavaria, Germany Reliable biological markers of the at-risk mental state for psychosis (ARMS) are crucial for early recognition and therapeutic intervention in ultra-high risk individuals. In this regard, previous studies showed that the ARMS is associated with subtle neuroanatomical abnormalities found in similar brain regions as in the established disorder. We employed multivariate analysis techniques in order to investigate whether different ARMS for psychosis and their clinical outcomes could be reliably diagnosed on the individual level based on structural brain alterations both at the cross-sectional and longitudinal level. Multivariate machine learning algorithms were applied on the structural magnetic resonance imaging (MRI) data of individuals in “early” (n= 24) and “late” (n= 27) ARMS of psychosis and healthy controls (HC, n = 25). The method's ability in predicting a subsequent transition to psychosis based on the baseline MRI data was evaluated in a subgroup of the ARMS population with available clinical follow-up information (transitions: n = 16, non-transitions: n = 18) compared to HC (n= 17). The specificity, sensitivity, accuracy, significance and generalizability of the methodology were evaluated by means of permutation analysis and five-fold cross-validation. Furthermore, we analyzed in a subgroup of 25 ARMS versus 28 HC individuals the significance and stability of whole-brain covariance patterns between brain volume changes and clinical changes over a follow-up period of 4 years and used these patterns to predict the clinical outcome in the ARMS group at the individual level. In the cross-sectional classification analysis of the baseline data, high cross-validated classification accuracies (>85%) were observed, (a) when we delineated the different at-risk mental states versus each other and versus HC and (b) when we tried to predict a subsequent transition or non-transition to psychosis. The longitudinal multivariate analysis revealed highly significant and stable patterns of differential volumetric changes that were most pronounced in the converter group but that were also detectable to a lesser degree in the non-converters versus HC.
113
Correlations between morphometric changes and clinical changes did not only consist of a pattern of accumulating volume losses in those that deteriorated clinically over time, but included also regions of brain volume expansion in those ARMS individuals who showed clinical improvement between baseline and follow-up. The individualized prediction of clinical change based on these patterns of longitudinal volumetric alteration achieved accuracies similar to baseline analysis (>80%). These findings suggest that different ARMS and their clinical outcomes may be reliably identified on an individual basis by assessing patterns of whole-brain neuroanatomical abnormalities. Furthermore, repeated MRI scanning may provide useful information regarding the neurobiological activity of the disease process but also possibly with respect to factors associated with resilience to the disease. Thus, both cross-sectional and longitudinal neuroanatomical classification systems may play an important role in the clinical management of the atrisk mental state and the early phases of psychosis.
doi:10.1016/j.schres.2010.02.035
Symposium 4 AN UPDATE ON THE NEXT WAVE OF SCHIZOPHRENIA THERAPEUTICS Co-Chairpersons: Nicholas J. Brandon, Christopher J. Schmidt Sunday, 11 April, 2010 - 3:30 pm - 5:30 pm
Overall Abstract: Current treatment of schizophrenia is dominated by atypical antipsychotics with mixed pharmacologies at the dopamine D2, serotonin 5HT2A and other receptors. A number of mechanisms are now entering clinical trials do not directly target the D2 or 5HT2A receptors but either directly or indirectly modulate glutamate receptor function. The glutamate hypothesis of schizophrenia suggests that N-Methyl-D-Aspartic acid (NMDA) receptor function is compromised in schizophrenia and may be responsible for the positive, negative and cognitive symptoms found in the disorder. We will provide an update on four novel mechanisms with an emphasis placed on their biology and pre-clinical efficacy profile. Kjell A. Svensson will discuss the Group II mGlu receptors (mGlu2 and mGlu3) as novel targets for schizophrenia. These receptors are located in forebrain and limbic brain regions and function as presynaptic autoreceptors to limit excessive glutamatergic neurotransmission. As excessive glutamatergic neurotransmission has been implicated in the pathophysiology of schizophrenia, stimulation of group II mGlu receptors may represent a potential target for the treatment of the disorders. In pre-clinical animal models, agonists of mGlu2/3 receptors and now more recently allosteric potentiators (PAM's) of mGlu2 receptors block many of the behavioral effects of NMDA receptor antagonists. Critically preliminary clinical data supports antipsychotic efficacy of an mGlu2/3 agonist prodrug in schizophrenic patients and an update on this clinical plan will be presented. Christopher J. Schmidt will discuss for the first time the type 1 glycine transporter (GlyT1) program at Pfizer. GlyT1 maintains synaptic concentrations of the NMDA receptor co-agonist glycine with inhibition predicted to increase synaptic glycine concentrations and thereby augment NMDA receptor mediated neurotransmission. He will introduce the GlyT1 inhibitor, PF-3463275, which has shown efficacy in cognition models in rodent and non-human primates and also been shown to potentiate the effects of risperidone in a pre-pulse inhibition model. This molecule has now entered Phase 1 studies in healthy volunteers where it was shown to be safe and well-tolerated at doses producing 2-3 fold elevations in CSF glycine. Pete Hutson will show how activation of mGlu5 receptors enhances NMDA receptor function provide another approach to treating schizophrenia.
Abstracts
disease phases from both the neurobiological and behavioral perspectives. In this context, imaging studies revealed that crosssectional and longitudinal abnormalities exist on the structural and functional brain dimensions of at-risk individuals and firstepisode patients. These findings have offered important insights into the brain pathology emerging during the transition from the prodromal state to the full-blown clinical picture of schizophrenia. Thus, the accumulating brain alterations described by recent neuroimaging studies may be interpreted within the concept of a late neurodevelopmental process that evolves when higher-order cortical areas are placed “under functional demand” during the critical transition from adolescence to adulthood. Beside these advances in the basic science of psychosis, the recent advent of multivariate pattern recognition techniques in the neuroimaging field has opened up new possibilities to derive valid biomarkers from, up to now, group-level statistical inferences that may allow for the individualized early recognition of the at-risk mental state and the prediction of disease transition. Thus, these findings may stir up the debate whether (a) structural and/or functional brain abnormalities represent reliable intermediate phenotypes, or “endophenotypes” of psychosis and whether (b) these imagingbased endophenotypes are sufficiently sensitive and specific markers of the underlying neurobiology and its behavioral expressions. A positive answer to these questions would allow neuroimaging techniques to cross the bridge between basic science and its potential clinical applications. The symposium aims to bring together leading experts from the field to present the state-of-the-art basic science aspects of neuroimaging research as well as its clinical perspectives regarding the application of individualized neurodiagnostic procedures for the early recognition of the high-risk states and the early phases of psychosis as well as the prediction of disease transition. References: Gur RE, Keshavan MS, Lawrie SM. Deconstructing psychosis with human brain imaging. Schizophr Bull. 2007 Jul;33 (4):921-31Sun D, van Erp TG, Thompson PM, Bearden CE, Daley M, Kushan L, Hardt ME, Nuechterlein KH, Toga AW, Cannon TD. Elucidating a Magnetic Resonance Imaging-Based Neuroanatomic Biomarker for Psychosis: Classification Analysis Using Probabilistic Brain Atlas and Machine Learning Algorithms. Biol Psychiatry. 2009; in press. Borgwardt SJ, Riecher-Rössler A, Dazzan P, Chitnis X, Aston J, Drewe M, Gschwandtner U, Haller S, Pflüger M, Rechsteiner E, Semenin V, Stieglitz RD, Radü EW, McGuire PK. Regional grey matter abnormalities in the At Risk Mental State. Biological Psychiatry.2007;15(61):1148-56.Koutsouleris N, Meisenzahl EM, Davatzikos C, Bottlender R, Frodl T, Scheuerecker J, Schmitt G, Zetzsche T, Decker P, Reiser M, Möller HJ, Gaser C. Use of neuroanatomical pattern classification to identify subjects in atrisk mental states of psychosis and predict disease transition. Arch Gen Psychiatry. 2009;66(7):700-12.
notypes are genetically mediated but are not on the causal pathways to psychosis (i.e., intermediate phenotypes), (b) other endophenotypes are not necessarily genetic but may still be intermediate phenotypes and (c) existing technologies can actually distinguish between schizophrenia and bipolar disorder, and between the relatives of patients with these disorders. I will conclude that endophenotypes are a useful concept in psychosis research, particularly in terms of helping to specify mechanisms but that researchers need to be careful about the use of these terms and the implications of these uses.
doi:10.1016/j.schres.2010.02.032
PROGRESSIVE BRAIN CHANGES ACROSS THE TRANSITION TO PSYCHOSIS: WHERE TO FROM HERE? Stephen Wood Melbourne Neuropsychiatry Centre, University of Melbourne and Melbourne Health Melbourne, Victoria, Australia Although the underlying neurobiology of emerging psychotic disorders is not well understood, there is a growing conviction that there are progressive brain changes in patients at clinical high risk for the illness. These changes are likely to begin well before the frank onset of the disorder and may continue for a number of years. In this talk, I will summarize the extant neuroimaging studies of people at clinical high risk for psychosis, both cross-sectional and longitudinal. By and large, there are few definitive markers that distinguish those who go on to develop the illness from those who do not. The two most consistently abnormal brain regions in schizophrenia research, the hippocampi and the lateral ventricles, do not show volumes significantly different to those of healthy controls prior to psychosis onset. However, frontal lobe measures (eg, cortical thickness in the anterior cingulate) do show promise, as do functional imaging measures sensitive to prefrontal cortex dysfunction. Further, longitudinal magnetic resonance imaging findings in individuals at clinical high risk show that there are excessive neuroanatomical changes in those who convert to psychosis. These aberrant changes are observed most prominently in medial temporal and prefrontal cortical regions. While the pathological processes underlying such changes remain unclear, speculatively they may reflect anomalies in genetic and/or other endogenous mechanisms responsible for brain maturation, the adverse effects of intense or prolonged stress, or other environmental factors. Active changes during transition to illness may present the potential to intervene and ameliorate these changes with potential benefit clinically.
doi:10.1016/j.schres.2010.02.031 doi:10.1016/j.schres.2010.02.033 ARE ENDOPHENOTYPES A USEFUL CONCEPT? Stephen Lawrie University of Edinburgh, Scotland, UK The rise of interest in endophenotypes appears related to frustration with the pace of progress in understanding schizophrenia and related disorders. We tend to think of endophenotypes, following Gottesman, as genetically mediated “hidden phenotypes” which are closely related to genetic risk factors but also raise the risk of clinical “exophenotypes”. In this presentation, I will challenge these views. I will demonstrate that (a) some endophe-
STRUCTURAL AND NEUROFUNCTIONAL ABNORMALITIES IN THE AT-RISK MENTAL STATE (ARMS) OF PSYCHOSIS Stefan Borgwardt University Hospital of Basel, Switzerland Over the past decade there has been an exponential growing of neuroimaging research in the early phases of psychosis. Despite the complexity of techniques worldwide engaged and the number of published papers, the clinical significance of anatomical or functional abnormalities is still mostly unknown. Thus, recent research
Abstracts
has started to longitudinally assess brain structure and function, with the aim to align functional imaging with clinical psychiatry. The aim of the study was to investigate brain structure and function in individuals with an At Risk Mental State (ARMS) relative to patients with first-episode psychosis (FE) and healthy volunteers (HC). The subjects were recruited within the Basel Early Detection of Psychosis Clinic (FEPSY) which has been established at the Psychiatric Outpatient Department, University Hospital Basel. Cross-sectional and longitudinal structural and functional magnetic resonance imaging (MRI) data were acquired using a 3.0 T scanner from individuals with an ARMS, similar to the PACE criteria, FE and HC. Images were processed and analysed using voxel based morphometry (VBM) and region-of-interest methods. Volumetric and neurofunctional abnormalities in areas that are also altered in schizophrenia were associated with specific abnormalities in people with an ARMS. However, results indicate that treatment with typical as well as atypical antipsychotics may also contribute to structural alterations. To conclude, some structural and neurofunctional abnormalities were specific to individuals with an ARMS and may be a correlate of their increased vulnerability to psychosis. Further changes within the ARMS appear to be associated with the subsequent onset of psychosis.
doi:10.1016/j.schres.2010.02.034
MRI-BASED BIOMARKERS FOR INDIVIDUALIZED NEURODIAGNOSTICS IN THE AT-RISK MENTAL STATE AND THE EARLY PHASE OF PSYCHOSIS Nikolaos Koutsouleris Ludwig-Maximilian-University, Munich, Bavaria, Germany Reliable biological markers of the at-risk mental state for psychosis (ARMS) are crucial for early recognition and therapeutic intervention in ultra-high risk individuals. In this regard, previous studies showed that the ARMS is associated with subtle neuroanatomical abnormalities found in similar brain regions as in the established disorder. We employed multivariate analysis techniques in order to investigate whether different ARMS for psychosis and their clinical outcomes could be reliably diagnosed on the individual level based on structural brain alterations both at the cross-sectional and longitudinal level. Multivariate machine learning algorithms were applied on the structural magnetic resonance imaging (MRI) data of individuals in “early” (n= 24) and “late” (n= 27) ARMS of psychosis and healthy controls (HC, n = 25). The method's ability in predicting a subsequent transition to psychosis based on the baseline MRI data was evaluated in a subgroup of the ARMS population with available clinical follow-up information (transitions: n = 16, non-transitions: n = 18) compared to HC (n= 17). The specificity, sensitivity, accuracy, significance and generalizability of the methodology were evaluated by means of permutation analysis and five-fold cross-validation. Furthermore, we analyzed in a subgroup of 25 ARMS versus 28 HC individuals the significance and stability of whole-brain covariance patterns between brain volume changes and clinical changes over a follow-up period of 4 years and used these patterns to predict the clinical outcome in the ARMS group at the individual level. In the cross-sectional classification analysis of the baseline data, high cross-validated classification accuracies (>85%) were observed, (a) when we delineated the different at-risk mental states versus each other and versus HC and (b) when we tried to predict a subsequent transition or non-transition to psychosis. The longitudinal multivariate analysis revealed highly significant and stable patterns of differential volumetric changes that were most pronounced in the converter group but that were also detectable to a lesser degree in the non-converters versus HC.
113
Correlations between morphometric changes and clinical changes did not only consist of a pattern of accumulating volume losses in those that deteriorated clinically over time, but included also regions of brain volume expansion in those ARMS individuals who showed clinical improvement between baseline and follow-up. The individualized prediction of clinical change based on these patterns of longitudinal volumetric alteration achieved accuracies similar to baseline analysis (>80%). These findings suggest that different ARMS and their clinical outcomes may be reliably identified on an individual basis by assessing patterns of whole-brain neuroanatomical abnormalities. Furthermore, repeated MRI scanning may provide useful information regarding the neurobiological activity of the disease process but also possibly with respect to factors associated with resilience to the disease. Thus, both cross-sectional and longitudinal neuroanatomical classification systems may play an important role in the clinical management of the atrisk mental state and the early phases of psychosis.
doi:10.1016/j.schres.2010.02.035
Symposium 4 AN UPDATE ON THE NEXT WAVE OF SCHIZOPHRENIA THERAPEUTICS Co-Chairpersons: Nicholas J. Brandon, Christopher J. Schmidt Sunday, 11 April, 2010 - 3:30 pm - 5:30 pm
Overall Abstract: Current treatment of schizophrenia is dominated by atypical antipsychotics with mixed pharmacologies at the dopamine D2, serotonin 5HT2A and other receptors. A number of mechanisms are now entering clinical trials do not directly target the D2 or 5HT2A receptors but either directly or indirectly modulate glutamate receptor function. The glutamate hypothesis of schizophrenia suggests that N-Methyl-D-Aspartic acid (NMDA) receptor function is compromised in schizophrenia and may be responsible for the positive, negative and cognitive symptoms found in the disorder. We will provide an update on four novel mechanisms with an emphasis placed on their biology and pre-clinical efficacy profile. Kjell A. Svensson will discuss the Group II mGlu receptors (mGlu2 and mGlu3) as novel targets for schizophrenia. These receptors are located in forebrain and limbic brain regions and function as presynaptic autoreceptors to limit excessive glutamatergic neurotransmission. As excessive glutamatergic neurotransmission has been implicated in the pathophysiology of schizophrenia, stimulation of group II mGlu receptors may represent a potential target for the treatment of the disorders. In pre-clinical animal models, agonists of mGlu2/3 receptors and now more recently allosteric potentiators (PAM's) of mGlu2 receptors block many of the behavioral effects of NMDA receptor antagonists. Critically preliminary clinical data supports antipsychotic efficacy of an mGlu2/3 agonist prodrug in schizophrenic patients and an update on this clinical plan will be presented. Christopher J. Schmidt will discuss for the first time the type 1 glycine transporter (GlyT1) program at Pfizer. GlyT1 maintains synaptic concentrations of the NMDA receptor co-agonist glycine with inhibition predicted to increase synaptic glycine concentrations and thereby augment NMDA receptor mediated neurotransmission. He will introduce the GlyT1 inhibitor, PF-3463275, which has shown efficacy in cognition models in rodent and non-human primates and also been shown to potentiate the effects of risperidone in a pre-pulse inhibition model. This molecule has now entered Phase 1 studies in healthy volunteers where it was shown to be safe and well-tolerated at doses producing 2-3 fold elevations in CSF glycine. Pete Hutson will show how activation of mGlu5 receptors enhances NMDA receptor function provide another approach to treating schizophrenia.