- Email: [email protected]
Poster #M173 STUDYING HEART ARRHYTHMIAS IN RELATION TO PSYCHOSIS (SHARP). INCREASED PREVALENCE OF CARDIAC ARRHYTHMIAS IN RECENT ONSET SCHIZOPHRENIA
Abstracts of the 4th Biennial Schizophrenia International Research Conference / Schizophrenia Research 153, Supplement 1 (2014) S1–S384
cantly increased concentrations of DPA (p<0.001; p<0.02), AA (p<0.001; p<0.001), LA (p=0.05; p=0.05), and NA (p=0.001; p<0.001) (p values reflect the Bonferrroni corrected post-hoc comparisons of patients vs controls and siblings vs controls, respectively). DHA was significantly increased in siblings only (NS; p=0.03). The concentrations of EPA were not significantly different between the three groups. Discussion: We find increased concentrations of the RBC PUFA DPA, AA, LA, and NA in both patients and their siblings as compared to controls. Importantly, the direction of change is similar in both patients and siblings for these four PUFA. To our best knowledge, this is the first study, in the largest sample to date, to investigate RBC PUFA in siblings of patients. Our findings largely contrast previous studies, which generally showed decreased levels of RBC PUFA in patients. However, differences between patient samples reflecting state of disorder, dietary patterns, medication use and drug abuse were identified as possible modifiers of PUFA concentrations, contributing to the heterogeneity present in the meta- analyses (Van der Kemp et al, 2012; Hoen et al, 2013). Interestingly, previous studies by Assies et al (2001) and Kemperman et al (2006), also investigating Dutch samples, showed trends towards increased concentrations for some PUFA. Possibly, regional differences in behavioural patterns (i.e. diet or drug abuse) may modify PUFA concentrations. Planned analyses will be used to further investigate these factors. In summary, our findings suggest that increased levels of RBC PUFA may be an intermediate phenotype for psychotic illness. Alternatively, increased levels of RBC PUFA may be the result of (shared) environmental factors, i.e. diet, social economic status, or cannabis use.
S253
control subjects, which impairs protein function and spine morphology. The subjects carrying this mutation had unusually low IQ and reductions in cortical gray matter thickness as compared to their peers. Discussion: In the mammalian brain most excitatory synapses are located on dendritic spines, tiny protrusions of dendrites. Changes in synapse numbers and shape have been intimately associated with cognitive function. Alterations in synapses and dendrites have also been extensively reported in schizophrenia. Many schizophrenia-associated molecules, such as NRG1, ERBB4, DTNBP1, and DISC1 have functions in dendrites and synapses, and many known regulators of neuronal synapses have recently been associated with schizophrenia. Studying these pathways could lead to a better understanding of disease neurobiology and could yield novel targets for treatments. By integrating multiple levels of analysis and diverse methodologies with translational and basic research, such studies will enhance the understanding of cellular and synaptic substrates of pathology in schizophrenia and will facilitate the development of novel treatments for cognitive deficits.
Poster #M173 STUDYING HEART ARRHYTHMIAS IN RELATION TO PSYCHOSIS (SHARP). INCREASED PREVALENCE OF CARDIAC ARRHYTHMIAS IN RECENT ONSET SCHIZOPHRENIA Arjen Sutterland 1,2 , Marieke Blom 3 , Lieuwe de Haan 4 , Hanno Tan 3 Academic Medical Centre, Early Psychosis Department, Amsterdam; 2 Arkin, Early Intervention Psychosis (VIP), Amsterdam; 3 Academic Medical Center, University of Amsterdam, the Netherlands; 4 University of Amsterdam 1
Poster #M172 MOLECULAR MECHANISMS UNDERLYING SYNAPTIC PATHOLOGY IN SCHIZOPHRENIA Peter Penzes Northwestern University Feinberg School of Medicine Background: Significant progress has been made over the recent years in understanding the genetic architecture, cellular substrates, brain circuits, and phenotypic profiles of schizophrenia. However, we are still far from understanding this disorder. While antipsychotic medications are effective in controlling the positive symptoms in most patients, cognitive symptoms are currently untreatable. Hence understanding the neurobiological bases of cognitive deficits in schizophrenia is essential for the development of novel therapeutic strategies for their treatment. Multiple lines of evidence from genetic, neuropathological, pharmacological, and imaging studies support a key role for abnormal synaptic connectivity in schizophrenia. Structural and functional imaging studies have consistently shown reductions in cortical gray matter and reduced functional connectivity. Amongst the ultrastructural changes thought to directly contribute to these abnormalities are reductions in synapse and dendritic spine density. Because cognitive function and dysfunction in humans and animal models have been intimately linked to synapse structure and function, cognitive deficits are thought to be most closely associated with alterations in synapses. Mounting evidence indicates that many schizophrenia risk genes encode proteins that affect synapse structure and function. Conversely, many known regulators of synapses have been associated with schizophrenia. This strongly supports the model that perturbations in the molecular network underlying synapse development and plasticity are critically involved in the pathogenesis of schizophrenia. Methods: We have used a multidisciplinary and multi-level combination of molecular and cellular approaches, cellular confocal and two-photon imaging, neuronal culture models, knockout mice, as well as genetic approaches and brain imaging in humans. Results: In this talk I will discuss recent findings from our laboratory that implicate molecules previously associated with schizophrenia by human genetic and postmortem neuropathological studies in the regulation of neuronal dendrites and synapses. One of these molecules is the protein product of the KALRN gene, which interacts with proteins encoded by the schizophrenia susceptibility genes DISC1, NRG1 and ERBB4, to regulate spine and dendrite plasticity. Inactivation of the KALRN gene in mice leads to a post-adolescent emergence of frontal cortical spine loss, cortical thinning, cognitive deficits, and other schizophrenia-related behavioral phenotypes. We also identified a novel mutation in the spine plasticity gene KALRN in a subject with schizophrenia and his sibling, but not in
Background: In schizophrenia an increased risk of sudden cardiac death has been shown (Heart 2010), which has traditionally been associated with increased prevalence of prolonged corrected QT (QTc) interval and cardiovascular risk factors (Glassman 2005, Fan 2013). However defective ion channels have been implicated as well in the pathophysiology of schizophrenia (Imbrici 2013). Specifically, genetic defects in the potassium and calcium gene (Somers 2012 & Ripke 2013) and autoimmune antibodies against the potassium channel have been associated with an increased risk of schizophrenia (Martinez 2013). Malfunctioning of several ion channels (potassium, sodium and calcium) has been implicated in cardiac arrhythmias (Wilde 2013). Importantly, various drugs (including some psychotropic drugs) could increase the risk of cardiac arrhythmias. Methods: We included 295 subjects with recent onset schizophrenia, who underwent ECG during admission between 2006 and 2012 to screen all for signs of Cardiac Arrhythmias and prolonged QTc interval. All patients who had an ECG suspect for Cardiac Arrhythmias were asked to be seen by a cardiologist to perform a provocation test to diagnose/exclude Cardiac Arrhythmias. Of patients diagnosed with a cardiac arrhythmia, we ask informed consent to screen for genetic defects and autoimmune antibodies against the potassium and sodium channel, which could underlie this disorder. Also we included a healthy control group of approximately the same age without psychiatric disorder. Results: Analysis of the ECG’s of 295 patients revealed a remarkably high proportion of suspected Cardiac Arrhythmias, namely 6%. Apart from that, 3% of patients had a prolonged QTc interval. Correlations with clinical measures will be presented. All patients with an ECG were asked for additional analysis described above. These analyses and the comparison with the healthy control group are currently analyzed and will be presented. Discussion: This study shows that in a considerable subset of patients with recent onset schizophrenia have an ECG suggestive of a cardiac arrhythmia or have a prolonged QTc interval. If a cardiac arrhythmia is confirmed in these patients, this may imply that there is a common pathophysiologic mechanism between cardiac arrhythmias and schizophrenia. Specifically, malfunctioning ion channels could be a pathofysiological factor in both clinical entities. This is relevant to prevent sudden cardiac death. Several antipsychotic medications used by these patients pose an increased threat of provoking ventricular arrhythmias. Accordingly, these drugs must be avoided in these patients, and alternative drugs must be sought. In a subset of these patients, preventive implantation of an implantable cardioverter defibrillator (ICD) may be necessary. Furthermore, unveiling the pathophysiologic mechanism can prompt development of a treatment targeting the underlying problem in this subset of patients with schizophrenia and the cardiac arrhythmia.
cantly increased concentrations of DPA (p<0.001; p<0.02), AA (p<0.001; p<0.001), LA (p=0.05; p=0.05), and NA (p=0.001; p<0.001) (p values reflect the Bonferrroni corrected post-hoc comparisons of patients vs controls and siblings vs controls, respectively). DHA was significantly increased in siblings only (NS; p=0.03). The concentrations of EPA were not significantly different between the three groups. Discussion: We find increased concentrations of the RBC PUFA DPA, AA, LA, and NA in both patients and their siblings as compared to controls. Importantly, the direction of change is similar in both patients and siblings for these four PUFA. To our best knowledge, this is the first study, in the largest sample to date, to investigate RBC PUFA in siblings of patients. Our findings largely contrast previous studies, which generally showed decreased levels of RBC PUFA in patients. However, differences between patient samples reflecting state of disorder, dietary patterns, medication use and drug abuse were identified as possible modifiers of PUFA concentrations, contributing to the heterogeneity present in the meta- analyses (Van der Kemp et al, 2012; Hoen et al, 2013). Interestingly, previous studies by Assies et al (2001) and Kemperman et al (2006), also investigating Dutch samples, showed trends towards increased concentrations for some PUFA. Possibly, regional differences in behavioural patterns (i.e. diet or drug abuse) may modify PUFA concentrations. Planned analyses will be used to further investigate these factors. In summary, our findings suggest that increased levels of RBC PUFA may be an intermediate phenotype for psychotic illness. Alternatively, increased levels of RBC PUFA may be the result of (shared) environmental factors, i.e. diet, social economic status, or cannabis use.
S253
control subjects, which impairs protein function and spine morphology. The subjects carrying this mutation had unusually low IQ and reductions in cortical gray matter thickness as compared to their peers. Discussion: In the mammalian brain most excitatory synapses are located on dendritic spines, tiny protrusions of dendrites. Changes in synapse numbers and shape have been intimately associated with cognitive function. Alterations in synapses and dendrites have also been extensively reported in schizophrenia. Many schizophrenia-associated molecules, such as NRG1, ERBB4, DTNBP1, and DISC1 have functions in dendrites and synapses, and many known regulators of neuronal synapses have recently been associated with schizophrenia. Studying these pathways could lead to a better understanding of disease neurobiology and could yield novel targets for treatments. By integrating multiple levels of analysis and diverse methodologies with translational and basic research, such studies will enhance the understanding of cellular and synaptic substrates of pathology in schizophrenia and will facilitate the development of novel treatments for cognitive deficits.
Poster #M173 STUDYING HEART ARRHYTHMIAS IN RELATION TO PSYCHOSIS (SHARP). INCREASED PREVALENCE OF CARDIAC ARRHYTHMIAS IN RECENT ONSET SCHIZOPHRENIA Arjen Sutterland 1,2 , Marieke Blom 3 , Lieuwe de Haan 4 , Hanno Tan 3 Academic Medical Centre, Early Psychosis Department, Amsterdam; 2 Arkin, Early Intervention Psychosis (VIP), Amsterdam; 3 Academic Medical Center, University of Amsterdam, the Netherlands; 4 University of Amsterdam 1
Poster #M172 MOLECULAR MECHANISMS UNDERLYING SYNAPTIC PATHOLOGY IN SCHIZOPHRENIA Peter Penzes Northwestern University Feinberg School of Medicine Background: Significant progress has been made over the recent years in understanding the genetic architecture, cellular substrates, brain circuits, and phenotypic profiles of schizophrenia. However, we are still far from understanding this disorder. While antipsychotic medications are effective in controlling the positive symptoms in most patients, cognitive symptoms are currently untreatable. Hence understanding the neurobiological bases of cognitive deficits in schizophrenia is essential for the development of novel therapeutic strategies for their treatment. Multiple lines of evidence from genetic, neuropathological, pharmacological, and imaging studies support a key role for abnormal synaptic connectivity in schizophrenia. Structural and functional imaging studies have consistently shown reductions in cortical gray matter and reduced functional connectivity. Amongst the ultrastructural changes thought to directly contribute to these abnormalities are reductions in synapse and dendritic spine density. Because cognitive function and dysfunction in humans and animal models have been intimately linked to synapse structure and function, cognitive deficits are thought to be most closely associated with alterations in synapses. Mounting evidence indicates that many schizophrenia risk genes encode proteins that affect synapse structure and function. Conversely, many known regulators of synapses have been associated with schizophrenia. This strongly supports the model that perturbations in the molecular network underlying synapse development and plasticity are critically involved in the pathogenesis of schizophrenia. Methods: We have used a multidisciplinary and multi-level combination of molecular and cellular approaches, cellular confocal and two-photon imaging, neuronal culture models, knockout mice, as well as genetic approaches and brain imaging in humans. Results: In this talk I will discuss recent findings from our laboratory that implicate molecules previously associated with schizophrenia by human genetic and postmortem neuropathological studies in the regulation of neuronal dendrites and synapses. One of these molecules is the protein product of the KALRN gene, which interacts with proteins encoded by the schizophrenia susceptibility genes DISC1, NRG1 and ERBB4, to regulate spine and dendrite plasticity. Inactivation of the KALRN gene in mice leads to a post-adolescent emergence of frontal cortical spine loss, cortical thinning, cognitive deficits, and other schizophrenia-related behavioral phenotypes. We also identified a novel mutation in the spine plasticity gene KALRN in a subject with schizophrenia and his sibling, but not in
Background: In schizophrenia an increased risk of sudden cardiac death has been shown (Heart 2010), which has traditionally been associated with increased prevalence of prolonged corrected QT (QTc) interval and cardiovascular risk factors (Glassman 2005, Fan 2013). However defective ion channels have been implicated as well in the pathophysiology of schizophrenia (Imbrici 2013). Specifically, genetic defects in the potassium and calcium gene (Somers 2012 & Ripke 2013) and autoimmune antibodies against the potassium channel have been associated with an increased risk of schizophrenia (Martinez 2013). Malfunctioning of several ion channels (potassium, sodium and calcium) has been implicated in cardiac arrhythmias (Wilde 2013). Importantly, various drugs (including some psychotropic drugs) could increase the risk of cardiac arrhythmias. Methods: We included 295 subjects with recent onset schizophrenia, who underwent ECG during admission between 2006 and 2012 to screen all for signs of Cardiac Arrhythmias and prolonged QTc interval. All patients who had an ECG suspect for Cardiac Arrhythmias were asked to be seen by a cardiologist to perform a provocation test to diagnose/exclude Cardiac Arrhythmias. Of patients diagnosed with a cardiac arrhythmia, we ask informed consent to screen for genetic defects and autoimmune antibodies against the potassium and sodium channel, which could underlie this disorder. Also we included a healthy control group of approximately the same age without psychiatric disorder. Results: Analysis of the ECG’s of 295 patients revealed a remarkably high proportion of suspected Cardiac Arrhythmias, namely 6%. Apart from that, 3% of patients had a prolonged QTc interval. Correlations with clinical measures will be presented. All patients with an ECG were asked for additional analysis described above. These analyses and the comparison with the healthy control group are currently analyzed and will be presented. Discussion: This study shows that in a considerable subset of patients with recent onset schizophrenia have an ECG suggestive of a cardiac arrhythmia or have a prolonged QTc interval. If a cardiac arrhythmia is confirmed in these patients, this may imply that there is a common pathophysiologic mechanism between cardiac arrhythmias and schizophrenia. Specifically, malfunctioning ion channels could be a pathofysiological factor in both clinical entities. This is relevant to prevent sudden cardiac death. Several antipsychotic medications used by these patients pose an increased threat of provoking ventricular arrhythmias. Accordingly, these drugs must be avoided in these patients, and alternative drugs must be sought. In a subset of these patients, preventive implantation of an implantable cardioverter defibrillator (ICD) may be necessary. Furthermore, unveiling the pathophysiologic mechanism can prompt development of a treatment targeting the underlying problem in this subset of patients with schizophrenia and the cardiac arrhythmia.