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NIACIN SENSITIVITY INCREASED IN AT RISK MENTAL STATE PATIENTS CONVERTING TO PSYCHOSIS WITHIN ONE YEAR
254
Abstracts
and Raftery, 2003) was performed to reduce the lipidomic data into a subset of 16 clusters. We used linear mixed models to analyze the effect of diagnosis on lipid cluster variables after adjusting for antipsychotic medication use, nutritional variables, smoking, obesity, waist circumference, and type 2 diabetes. Results: Compared with their matched controls, persons with schizophrenia had significantly higher lipid levels in six clusters which represent mainly the shorter and saturated triacylglycerols. The effect of schizophrenia became even more pronounced in the linear mixed model: after adjusting for medication, lifestylerelated variables and type 2 diabetes, schizophrenia remained independently associated with higher levels with these six clusters (P < 0.01 in each cluster). Lipid abnormalities were much less pronounced in persons with ONAP, and persons with affective psychosis did not differ from their matched controls. Clusters in which persons with schizophrenia had the most pronounced elevations strongly correlated with gamma-glutamyl transferase values. Discussion: Our findings suggest that specific lipid abnormalities related to saturated triglycerides are specifically associated with schizophrenia. These affected lipids are known to be enriched in Very Low Density Lipoprotein (VLDL) particles (Kotronen et al. 2009), thus VLDL secretion from liver and the amount of liver fat may play a role in schizophrenia. This is also supported by our observation that the schizophrenia-affected lipid clusters associated with gamma-glutamyl transferase values. References: Fraley C and Raftery AE. Enhanced Software for Modelbased Clustering, Density Estimation, and Discriminant Analysis: mclust. J. Classif. 2003; 20: 263-286. Kotronen A, et al.. Serum saturated fatty acids containing triacylglycerols are better markers of insulin resistance than total serum triacylglycerol concentrations. Diabetologia. 2009 Apr;52(4):684-90. Oresic M, et al. Dysregulation of lipid and amino acid metabolism precedes islet autoimmunity in children who later progress to type 1 diabetes. J Exp Med. 2008;205 (13):2975-84. Perälä J, et al. Lifetime prevalence of psychotic and bipolar I disorders in a general population. Arch Gen Psychiatry 2007; 64:19-28. Suvisaari JM, et al. Metabolic syndrome among persons with schizophrenia and other psychotic disorders in a general population survey. J Clin Psychiatry 2007; 68:1045-55.
doi:10.1016/j.schres.2010.02.395
Poster 168 NIACIN SENSITIVITY INCREASED IN AT RISK MENTAL STATE PATIENTS CONVERTING TO PSYCHOSIS WITHIN ONE YEAR Stefan Smesny1, Berko Milleit1, Miriam R. Schaefer2,3, Christine Milleit1, Gregor Berger4, Heinrich Sauer1, Paul G. Amminger2,3 1 Department of Psychiatry, University Hospital Jena, Thuringia, Germany; 2ORYGEN Research Centre, University Hospital Melbourne, Victoria, Australia; 3Department of Child and Adolescent Psychiatry, University Hospital Vienna, Austria; 4Integrierte Psychiatrie Winterthur IPW Winterthur, Switzerland Background: Attenuated flush response to local methylnicotinate (AMN, niacin) skin stimulation is commonly reported in people suffering acute psychotic episodes and was related to a depletion of polyunsaturated fatty acids (PUFA) in cell membranes and disturbed prostaglandin formation. We investigated niacin sensitivity in ultra high-risk (UHR) subjects and performed follow up investigations over one year after baseline assessments assuming that processes leading to the flush deficit are active and changing during the at-risk and initial acute state of disorder.
Methods: AMN (0.1 M, 0.01 M, 0.001 M and 0.0001 M) was applied to the forearm skin in 81 UHR patients (13 transitions/first followup year). Skin flushing was visually assessed in 5 min intervals over 20 min using the 7-point Berger-Rating-Scale. Results: In those patients who developed an acute psychotic episode within one year after baseline testing, stimulation with the 0.0001 M AMN concentration revealed an increased skin flush response at baseline. Discussion: This unexpected finding suggests a different (i.e. changing) pattern of niacin sensitivity in people at risk to develop psychosis and people currently suffering an acute psychotic episode. Whereas increased skin flushing during the risk state might indicate efforts to compensate processes leading to psychosis (e.g. increased mobilisation of PUFA as prostaglandin precursors), decreased flush response during psychosis might indicate exhausted PUFA resources ("precursor deficiency model"). The shifting pattern of niacin sensitivity points against endophenotype properties of niacin sensitivity. The predictive value of increased niacin sensitivity in UHR subjects in terms of response to fatty acid supplementation is worth to be further investigated.
doi:10.1016/j.schres.2010.02.396
Poster 169 DECREASED NEUREGULIN C-TERMINAL FRAGMENTS IN SCHIZOPHRENIA PREFRONTAL CORTEX BRODMANN'S AREA 6 Adel Barakat1, Elizabeth L. Scarr2,3, Brian Dean2,3, Genevieve Evin1,2 Department of Pathology, University of Melbourne Parkville , Victoria , Australia; 2Centre for Neuroscience, University of Melbourne Parkville , Victoria, Australia; 3Mental Health Research Institute Parkville, Victoria, Australia 1
Background: The molecular changes that contribute to the pathophysiology of schizophrenia (SCZ) remain poorly understood. Genetic studies, in several populations, have linked polymorphisms in the neuregulin 1 gene (NRG1) to SCZ (Harrison & Law, Biol Psychiatry 2006, 60:132-40; Stefansson et al. Ann Med 2004, 36, 62-71; Tosato et al, Schizo Bull 31, 613–617, 2005). A missense mutation in the transmembrane domain of NRG1 has also been associated with SCZ (Walss-Bass et al, Biol Psychiatry 2006, 60, 548-553). In the brain, NRG1 is expressed as a membrane-bound precursor protein that can be cleaved sequentially by BACE-1 and g-secretase (Mei & Xiong, Nat Rev Neurosci 2008, 9, 437-52). The first cleavage by BACE-1 releases soluble NRG1which, upon binding to erbB tyrosine kinase receptors triggers a cascade of downstream signalling events resulting in activation of GABA, NMDA, and nicotinic receptors. The second cleavage carried out by g-secretase releases the intracellular domain of NRG1, which translocates to the nucleus and activates gene transcription. Recent studies with mouse models have demonstrated that impaired NRG1/ErbB signalling, due to a knockout of either BACE-1 (Savonenko et al, Proc Natl Acad Sci USA2008, 105, 558590) or of APH1b g-secretase subunit gene leads to SCZ-like phenotypes that can be rescued by antipsychotics (Dejaegere et al, Proc Natl Acad Sci USA 2008, 105, 9775-80). Hypotheses: We hypothesized that the proteolytic processing of NRG1 may be altered in the prefrontal cortex of patients with SCZ. Since BACE1 expression may be controlled by muscarinic acetylcholine receptors (Züchner et al, J Neurosci Res 2004, 77, 250-7) and muscarinic M1 receptors (CHRM1) have been shown to be decreased by approximately 75% in a subpopulation of SCZ patients, termed the muscarinic receptor deficit schizophrenia (MRDS; Scarr et al, Mol Psychiatry 2009, 14, 1017-23), we proposed that subjects with MRDS would have decreased BACE1 expression or activity and thus, NRG1 proteolytic processing.
Abstracts
and Raftery, 2003) was performed to reduce the lipidomic data into a subset of 16 clusters. We used linear mixed models to analyze the effect of diagnosis on lipid cluster variables after adjusting for antipsychotic medication use, nutritional variables, smoking, obesity, waist circumference, and type 2 diabetes. Results: Compared with their matched controls, persons with schizophrenia had significantly higher lipid levels in six clusters which represent mainly the shorter and saturated triacylglycerols. The effect of schizophrenia became even more pronounced in the linear mixed model: after adjusting for medication, lifestylerelated variables and type 2 diabetes, schizophrenia remained independently associated with higher levels with these six clusters (P < 0.01 in each cluster). Lipid abnormalities were much less pronounced in persons with ONAP, and persons with affective psychosis did not differ from their matched controls. Clusters in which persons with schizophrenia had the most pronounced elevations strongly correlated with gamma-glutamyl transferase values. Discussion: Our findings suggest that specific lipid abnormalities related to saturated triglycerides are specifically associated with schizophrenia. These affected lipids are known to be enriched in Very Low Density Lipoprotein (VLDL) particles (Kotronen et al. 2009), thus VLDL secretion from liver and the amount of liver fat may play a role in schizophrenia. This is also supported by our observation that the schizophrenia-affected lipid clusters associated with gamma-glutamyl transferase values. References: Fraley C and Raftery AE. Enhanced Software for Modelbased Clustering, Density Estimation, and Discriminant Analysis: mclust. J. Classif. 2003; 20: 263-286. Kotronen A, et al.. Serum saturated fatty acids containing triacylglycerols are better markers of insulin resistance than total serum triacylglycerol concentrations. Diabetologia. 2009 Apr;52(4):684-90. Oresic M, et al. Dysregulation of lipid and amino acid metabolism precedes islet autoimmunity in children who later progress to type 1 diabetes. J Exp Med. 2008;205 (13):2975-84. Perälä J, et al. Lifetime prevalence of psychotic and bipolar I disorders in a general population. Arch Gen Psychiatry 2007; 64:19-28. Suvisaari JM, et al. Metabolic syndrome among persons with schizophrenia and other psychotic disorders in a general population survey. J Clin Psychiatry 2007; 68:1045-55.
doi:10.1016/j.schres.2010.02.395
Poster 168 NIACIN SENSITIVITY INCREASED IN AT RISK MENTAL STATE PATIENTS CONVERTING TO PSYCHOSIS WITHIN ONE YEAR Stefan Smesny1, Berko Milleit1, Miriam R. Schaefer2,3, Christine Milleit1, Gregor Berger4, Heinrich Sauer1, Paul G. Amminger2,3 1 Department of Psychiatry, University Hospital Jena, Thuringia, Germany; 2ORYGEN Research Centre, University Hospital Melbourne, Victoria, Australia; 3Department of Child and Adolescent Psychiatry, University Hospital Vienna, Austria; 4Integrierte Psychiatrie Winterthur IPW Winterthur, Switzerland Background: Attenuated flush response to local methylnicotinate (AMN, niacin) skin stimulation is commonly reported in people suffering acute psychotic episodes and was related to a depletion of polyunsaturated fatty acids (PUFA) in cell membranes and disturbed prostaglandin formation. We investigated niacin sensitivity in ultra high-risk (UHR) subjects and performed follow up investigations over one year after baseline assessments assuming that processes leading to the flush deficit are active and changing during the at-risk and initial acute state of disorder.
Methods: AMN (0.1 M, 0.01 M, 0.001 M and 0.0001 M) was applied to the forearm skin in 81 UHR patients (13 transitions/first followup year). Skin flushing was visually assessed in 5 min intervals over 20 min using the 7-point Berger-Rating-Scale. Results: In those patients who developed an acute psychotic episode within one year after baseline testing, stimulation with the 0.0001 M AMN concentration revealed an increased skin flush response at baseline. Discussion: This unexpected finding suggests a different (i.e. changing) pattern of niacin sensitivity in people at risk to develop psychosis and people currently suffering an acute psychotic episode. Whereas increased skin flushing during the risk state might indicate efforts to compensate processes leading to psychosis (e.g. increased mobilisation of PUFA as prostaglandin precursors), decreased flush response during psychosis might indicate exhausted PUFA resources ("precursor deficiency model"). The shifting pattern of niacin sensitivity points against endophenotype properties of niacin sensitivity. The predictive value of increased niacin sensitivity in UHR subjects in terms of response to fatty acid supplementation is worth to be further investigated.
doi:10.1016/j.schres.2010.02.396
Poster 169 DECREASED NEUREGULIN C-TERMINAL FRAGMENTS IN SCHIZOPHRENIA PREFRONTAL CORTEX BRODMANN'S AREA 6 Adel Barakat1, Elizabeth L. Scarr2,3, Brian Dean2,3, Genevieve Evin1,2 Department of Pathology, University of Melbourne Parkville , Victoria , Australia; 2Centre for Neuroscience, University of Melbourne Parkville , Victoria, Australia; 3Mental Health Research Institute Parkville, Victoria, Australia 1
Background: The molecular changes that contribute to the pathophysiology of schizophrenia (SCZ) remain poorly understood. Genetic studies, in several populations, have linked polymorphisms in the neuregulin 1 gene (NRG1) to SCZ (Harrison & Law, Biol Psychiatry 2006, 60:132-40; Stefansson et al. Ann Med 2004, 36, 62-71; Tosato et al, Schizo Bull 31, 613–617, 2005). A missense mutation in the transmembrane domain of NRG1 has also been associated with SCZ (Walss-Bass et al, Biol Psychiatry 2006, 60, 548-553). In the brain, NRG1 is expressed as a membrane-bound precursor protein that can be cleaved sequentially by BACE-1 and g-secretase (Mei & Xiong, Nat Rev Neurosci 2008, 9, 437-52). The first cleavage by BACE-1 releases soluble NRG1which, upon binding to erbB tyrosine kinase receptors triggers a cascade of downstream signalling events resulting in activation of GABA, NMDA, and nicotinic receptors. The second cleavage carried out by g-secretase releases the intracellular domain of NRG1, which translocates to the nucleus and activates gene transcription. Recent studies with mouse models have demonstrated that impaired NRG1/ErbB signalling, due to a knockout of either BACE-1 (Savonenko et al, Proc Natl Acad Sci USA2008, 105, 558590) or of APH1b g-secretase subunit gene leads to SCZ-like phenotypes that can be rescued by antipsychotics (Dejaegere et al, Proc Natl Acad Sci USA 2008, 105, 9775-80). Hypotheses: We hypothesized that the proteolytic processing of NRG1 may be altered in the prefrontal cortex of patients with SCZ. Since BACE1 expression may be controlled by muscarinic acetylcholine receptors (Züchner et al, J Neurosci Res 2004, 77, 250-7) and muscarinic M1 receptors (CHRM1) have been shown to be decreased by approximately 75% in a subpopulation of SCZ patients, termed the muscarinic receptor deficit schizophrenia (MRDS; Scarr et al, Mol Psychiatry 2009, 14, 1017-23), we proposed that subjects with MRDS would have decreased BACE1 expression or activity and thus, NRG1 proteolytic processing.