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PL.03.01 The schizophrenia paradigm: a hundred-year challenge
Sl73
Plenary lectures
PL.Ol Plenary lecture IpL.01.011 The neurobiological basis of addictive behaviour: a genetic perspective G. Schumann1 '. 1King's College London, Interdisciplinary Research Group Addiction MRC-SGDP-Centre, London, United Kingdom Addictions are common psychiatric disorders that exert a very high cost to the individual and to society. They are a result of the interplay of multiple behavioural, genetic and environmental factors. Addictive behaviour is characterized by phenotypic and genetic heterogeneity as well as polygenicity, implying a contribution of different neurobiological mechanisms to the clinical diagnosis. Therefore, treatments for most addiction-related disorders are often only partially effective, with a substantial proportion of patients failing to respond. To address heterogeneity and polygenicity, strategies have been developed to identify more homogeneous subgroups of patients and to characterize genes contributing to their (endo-) phenotype. In this presentation, gene identification strategies using whole genome approaches as well as translational candidate gene strategies to identify the genetic and neurobiological basis of addictive behaviour will be presented, their mechanistic function will be characterised and their association with endophenotypes relevant for addiction-related disorders will be described. Applying these strategies in a translational context aims at improving therapeutic response by the identification of subgroups of addiction patients for individualized, targeted treatment strategies. Finally, a European Integrated Project "IMAGEN", which investigates reinforcement-related behaviour using multicentric gene x neuroimaging in 2000 adolescents will be presented. This project aims to integrate the methodical approaches discussed above in order to identify the genetic and neurobiological basis of behavioural traits relevant to the development of addictions. References
[1] Wong CC, Schumann G. Genetics of addictions: strategies for addressing heterogeneity and po1ygenicity of substance use disorders (review). Phi10s Trans R Soc Lond B Bio1 Sci. 2008 Oct 12; 363(1507): 3213-22 [2] Schumann G, Johann M, Frank J, Preuss D, Dahmen N, Laucht M, Rietsche1 M, Rujescu D, Lourdusamy A, Clarke TK, Krause K, Dyer A, Depner M, Wellek S, Treutlein J, Szegedi A, Gieg1ing I, Cichon S, B10meyer D, Heinz A, Heath S, Lathrop M, Wodarz N, Soyka M, Spanage1 R, Mann K. Systematic analysis of glutamatergic neurotransmission genes in alcohol dependence and adolescent risky drinking behavior. Arch Gen Psychiatry. 2008 Jill; 65(7): 826-38. [3] Spanage1 R, Pendyala G, Abarca C, Zghoill T, Sanchis-Segura C, Magn~Jne MC, Lascorz J, Depner M, Ho1zberg D, Soyka M, SchreIber S, Matsuda F, Lathrop M, Schumann G, Albrecht U. The clock gene Per2 influences the glutamatergic system and modillates alcohol consumption. Nat Med. 2005 Jan; 11(1): 35-42.
PL.02 ECNP Neuropsychopharmacology Award lecture IpL.02.011 New mechanism responsible for drug addiction: uncoupling between noradrenergic and serotonergic neurons
J. Tassin1 '.
1 College
de France, Paris, France
A challenge in drug dependence is to delineate long-term behavioral and neurochemical modifications induced by drugs of abuse. In rodents, drugs of abuse induce locomotor hyperactivity, and repeating injections enhances this response. This effect, called behavioral sensitization, persists many months after the last administration, thus mimicking long-term sensitivity to drugs observed in human addicts. Although addictive properties of drugs of abuse are generally considered to be mediated by an increased release of dopamine in the ventral striatum, recent pharmacological and genetic experiments indicate an implication of al b-adrenergic receptors in behavioral and rewarding responses to psychostimulants and opiates. However, it was also shown that not only noradrenergic but also serotonergic systems, through 5-HT2A receptors, are controlling behavioral effects of drugs of abuse. Finally, experiments performed in animals knockout for alb-adrenergic or 5-HT2A receptors indicated that noradrenergic and serotonergic neurons, besides their activating effects, inhibit each other by means of the stimulation of alb-adrenergic and 5-HT2A receptors and that this mutual inhibition vanishes in wild type mice with repeated injections of psychostimulants, opiates, alcohol or tobacco. Uncoupling induced by repeated treatments with drugs of abuse installs a stable sensitization of noradrenergic and serotonergic neurons, thus explaining an increased reactivity of dopaminergic neurons and behavioral sensitization. We propose that noradrenergic/serotonergic uncoupling is a common stable neurochemical consequence of repeated drugs of abuse which may also occur during chronic stressful situations and facilitate the onset of mental illness. Drug consumption would facilitate an artificial re-coupling of these neurons, thus bringing a temporary relief.
PL.03 Plenary lecture IpL.03.011 The schizophrenia paradigm: a hundred-year challenge
W. Carpenter Jr. 1 '. 1 University of Maryland, Maryland Psychiatric Research Center, Baltimore, USA Kraepelin presented dementia praecox as a disease entity and, together with manic-depressive illness formulated the dichotomous view of psychotic illnesses that remains a primary influence today. Bleuler reinforced the disease entity construct by observing dissociative pathology as fundamental in all cases. Schizophrenia as a disease entity has been the dominant paradigm applied in
S174
PL.03 Plenary lecture
research, treatment development and clinical practice. However, Bleuler's reference to "The Group of Schizophrenias" also implied a syndrome status. This results in a hundred-year challenge to define disease entities within the syndrome. Deficit schizophrenia has been proposed as a disease entity within the schizophrenia syndrome [1]. Clinical distinctions between deficit and non-deficit schizophrenia are robust and include reduced depression, suicide, and substance abuse in deficit schizophrenia. More important are the neuroimaging, post-mortem neuropathology, endophenotype, and environmental and genetic risk factor differences. Primary negative symptoms proved decisive for the deficit/nondeficit distinction. Rather than using this pathology only to identify a separate disease entity, the concept of domains of pathology is introduced [2,3] as a paradigm shift. The effectiveness of this alternative paradigm is illustrated by the FDA joining a consensus on domains of pathology as indications for drug approval and by the NIMH making a major investment in specific pathology domains within schizophrenia rather than the syndrome level investigation. This alternative paradigm is anticipated as a major innovation with DSM-V and nine domains are being considered as dimensions for schizophrenia and related psychoses. References [1] Kirkpatrick B, Buchanan RW, Ross DE and Carpenter WT. 2001 A separate disease within the syndrome of schizophrenia. Archives of General Psychiatry, 58: 165-171. [2] Strauss JS, Carpenter WT Jr, Bartko JJ. 1974 The diagnosis and understanding of schizophrenia. Part III. Speculations on the processes that underlie schizophrenic symptoms and signs. Schizophr Bull. Winter; (11): 61-9. [3] Carpenter WT, Buchanan Rw. 1989 Domains of psychopathology relevant to the study of etiology and treatment of schizophrenia. In: Schulz SC, Tamminga CT (eds.), Schizophrenia: Scientific Progress. Oxford University Press, New York, pp. 13-22.
Plenary lectures
PL.Ol Plenary lecture IpL.01.011 The neurobiological basis of addictive behaviour: a genetic perspective G. Schumann1 '. 1King's College London, Interdisciplinary Research Group Addiction MRC-SGDP-Centre, London, United Kingdom Addictions are common psychiatric disorders that exert a very high cost to the individual and to society. They are a result of the interplay of multiple behavioural, genetic and environmental factors. Addictive behaviour is characterized by phenotypic and genetic heterogeneity as well as polygenicity, implying a contribution of different neurobiological mechanisms to the clinical diagnosis. Therefore, treatments for most addiction-related disorders are often only partially effective, with a substantial proportion of patients failing to respond. To address heterogeneity and polygenicity, strategies have been developed to identify more homogeneous subgroups of patients and to characterize genes contributing to their (endo-) phenotype. In this presentation, gene identification strategies using whole genome approaches as well as translational candidate gene strategies to identify the genetic and neurobiological basis of addictive behaviour will be presented, their mechanistic function will be characterised and their association with endophenotypes relevant for addiction-related disorders will be described. Applying these strategies in a translational context aims at improving therapeutic response by the identification of subgroups of addiction patients for individualized, targeted treatment strategies. Finally, a European Integrated Project "IMAGEN", which investigates reinforcement-related behaviour using multicentric gene x neuroimaging in 2000 adolescents will be presented. This project aims to integrate the methodical approaches discussed above in order to identify the genetic and neurobiological basis of behavioural traits relevant to the development of addictions. References
[1] Wong CC, Schumann G. Genetics of addictions: strategies for addressing heterogeneity and po1ygenicity of substance use disorders (review). Phi10s Trans R Soc Lond B Bio1 Sci. 2008 Oct 12; 363(1507): 3213-22 [2] Schumann G, Johann M, Frank J, Preuss D, Dahmen N, Laucht M, Rietsche1 M, Rujescu D, Lourdusamy A, Clarke TK, Krause K, Dyer A, Depner M, Wellek S, Treutlein J, Szegedi A, Gieg1ing I, Cichon S, B10meyer D, Heinz A, Heath S, Lathrop M, Wodarz N, Soyka M, Spanage1 R, Mann K. Systematic analysis of glutamatergic neurotransmission genes in alcohol dependence and adolescent risky drinking behavior. Arch Gen Psychiatry. 2008 Jill; 65(7): 826-38. [3] Spanage1 R, Pendyala G, Abarca C, Zghoill T, Sanchis-Segura C, Magn~Jne MC, Lascorz J, Depner M, Ho1zberg D, Soyka M, SchreIber S, Matsuda F, Lathrop M, Schumann G, Albrecht U. The clock gene Per2 influences the glutamatergic system and modillates alcohol consumption. Nat Med. 2005 Jan; 11(1): 35-42.
PL.02 ECNP Neuropsychopharmacology Award lecture IpL.02.011 New mechanism responsible for drug addiction: uncoupling between noradrenergic and serotonergic neurons
J. Tassin1 '.
1 College
de France, Paris, France
A challenge in drug dependence is to delineate long-term behavioral and neurochemical modifications induced by drugs of abuse. In rodents, drugs of abuse induce locomotor hyperactivity, and repeating injections enhances this response. This effect, called behavioral sensitization, persists many months after the last administration, thus mimicking long-term sensitivity to drugs observed in human addicts. Although addictive properties of drugs of abuse are generally considered to be mediated by an increased release of dopamine in the ventral striatum, recent pharmacological and genetic experiments indicate an implication of al b-adrenergic receptors in behavioral and rewarding responses to psychostimulants and opiates. However, it was also shown that not only noradrenergic but also serotonergic systems, through 5-HT2A receptors, are controlling behavioral effects of drugs of abuse. Finally, experiments performed in animals knockout for alb-adrenergic or 5-HT2A receptors indicated that noradrenergic and serotonergic neurons, besides their activating effects, inhibit each other by means of the stimulation of alb-adrenergic and 5-HT2A receptors and that this mutual inhibition vanishes in wild type mice with repeated injections of psychostimulants, opiates, alcohol or tobacco. Uncoupling induced by repeated treatments with drugs of abuse installs a stable sensitization of noradrenergic and serotonergic neurons, thus explaining an increased reactivity of dopaminergic neurons and behavioral sensitization. We propose that noradrenergic/serotonergic uncoupling is a common stable neurochemical consequence of repeated drugs of abuse which may also occur during chronic stressful situations and facilitate the onset of mental illness. Drug consumption would facilitate an artificial re-coupling of these neurons, thus bringing a temporary relief.
PL.03 Plenary lecture IpL.03.011 The schizophrenia paradigm: a hundred-year challenge
W. Carpenter Jr. 1 '. 1 University of Maryland, Maryland Psychiatric Research Center, Baltimore, USA Kraepelin presented dementia praecox as a disease entity and, together with manic-depressive illness formulated the dichotomous view of psychotic illnesses that remains a primary influence today. Bleuler reinforced the disease entity construct by observing dissociative pathology as fundamental in all cases. Schizophrenia as a disease entity has been the dominant paradigm applied in
S174
PL.03 Plenary lecture
research, treatment development and clinical practice. However, Bleuler's reference to "The Group of Schizophrenias" also implied a syndrome status. This results in a hundred-year challenge to define disease entities within the syndrome. Deficit schizophrenia has been proposed as a disease entity within the schizophrenia syndrome [1]. Clinical distinctions between deficit and non-deficit schizophrenia are robust and include reduced depression, suicide, and substance abuse in deficit schizophrenia. More important are the neuroimaging, post-mortem neuropathology, endophenotype, and environmental and genetic risk factor differences. Primary negative symptoms proved decisive for the deficit/nondeficit distinction. Rather than using this pathology only to identify a separate disease entity, the concept of domains of pathology is introduced [2,3] as a paradigm shift. The effectiveness of this alternative paradigm is illustrated by the FDA joining a consensus on domains of pathology as indications for drug approval and by the NIMH making a major investment in specific pathology domains within schizophrenia rather than the syndrome level investigation. This alternative paradigm is anticipated as a major innovation with DSM-V and nine domains are being considered as dimensions for schizophrenia and related psychoses. References [1] Kirkpatrick B, Buchanan RW, Ross DE and Carpenter WT. 2001 A separate disease within the syndrome of schizophrenia. Archives of General Psychiatry, 58: 165-171. [2] Strauss JS, Carpenter WT Jr, Bartko JJ. 1974 The diagnosis and understanding of schizophrenia. Part III. Speculations on the processes that underlie schizophrenic symptoms and signs. Schizophr Bull. Winter; (11): 61-9. [3] Carpenter WT, Buchanan Rw. 1989 Domains of psychopathology relevant to the study of etiology and treatment of schizophrenia. In: Schulz SC, Tamminga CT (eds.), Schizophrenia: Scientific Progress. Oxford University Press, New York, pp. 13-22.