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PL.03 The schizophrenia paradigm: a hundred-year challenge
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Plenary lectures
PL.01. Plenary lecture PL.01 The endocannabinoids: functional roles and therapeutic opportunities R. Mechoulam ° . Hebrew University of Jerusalem, Faculty of Medicine, Jerusalem, Israel The major endocannabinoid, 2-arachidonoyl glycerol (2-AG) has been identified both in the central nervous system and in the periphery. Stressful stimuli – traumatic brain injury (TBI) for example – enhance brain 2-AG levels in mice. 2-AG, both of endogenous and exogenous origin, has been shown to be neuroprotective in closed head injury, ischemia and excitotoxicity in mice. These effects may derive from the ability of cannabinoids to act through various biochemical mechanisms, including inhibition of glutamate release or direct blockade of NMDA receptors, action as reactive oxygen species (ROS) scavengers, inhibition of proinflammatory cytokines and inhibition of NF-úB activation. 2-AG also helps repair the blood brain barrier after TBI. The endocannabinoids act via specific cannabinoid receptors, of which the CB1 receptors are most abundant in the CNS. We have shown that CB1 knockout mice display slower functional recovery after TBI and do not respond to treatment with 2-AG. Recently CB2 receptors have also been found to be formed in the brain, particularly in various pathological states. We assumed that the endocannabinoid system may be involved in the pathogenesis of hepatic encephalopathy, a neuropsychiatric syndrome induced by fulminant hepatic failure. Indeed in an animal model we found that brain levels of 2-AG are elevated. Administration of 2-AG or specific CB2 agonists improved neurological scores, activity and cognitive function. CB1 agonists were inactive. References [1] Mechoulam R, Panikashvili D, Shohami E, 2002, Cannabinoids and brain injury. Trends Mol Med 8, 58−61.
PL.02. ECNP Neuropsychopharmacology Award Lecture PL.02 Susceptibility or resilience to psychopathology? A question of stress, genes and balance E.R. De Kloet ° . Leiden University, Gorlaeus Laboratories Leiden/ Amsterdam Centre of Drug Research, Leiden, The Netherlands A fundamental question in the neuropsychopharmacology of affective disorders is how stress mediators that are crucial for health can change into harmful signals enhancing vulnerability to disease. To address this question I focus on cortisol. (1) Stress causes premature secretory bursts of cortisol, an adrenal hormone that is otherwise secreted in hourly pulses. The action of cortisol is mediated by mineralocorticoid (MR) and glucocorticoid receptors (GR) abundantly expressed in neurons
of hippocampus, amygdalae and frontal cortex. The receptors are transcription factors regulating gene transcription, but recently their rapid non-genomic action on glutamate transmission was discovered. MR participates in initial stress reactions important for appraisal and coping processes, while management of the later adaptive phase depends on GR. (2) Gene variants of MR and GR have been identified. The MR I180V variant shows loss of function and carriers display a strongly enhanced neuro-endocrine and autonomic responses to psychological stressors. Aged subjects carrying this polymorphism display prevalence of depressive symptoms suggesting the MR variant is a genetic risk factor. (3) Early life experience exerts through epigenomics lasting effects on MR/GR functioning underlying stress responsivity, cognitive performance and emotional arousal in later life. In conclusion, imbalance in stress mediators caused by genetic factors and early life experience is a characteristic feature of a vulnerable phenotype. This concept calls for recovery of the MR/GR balance as a therapeutic strategy to promote a mechanism of resilience still present in the diseased brain. Supported by KNAW and NWO. References [1] 2007, Nature Clin Endocrinol Metab 3, 168–179.
PL.03. Plenary lecture PL.03 The schizophrenia paradigm: a hundred-year challenge W.T. Carpenter Jr. ° . University of Maryland, Maryland Psychiatric Research Center, Baltimore, USA Kraepelin brought several putative diseases into the dementia praecox disease entity construct. Dissociative and avolitional pathology were described as the two primary clinical features arising from the same etiopathophysiology. Blueler reinforced the single disease entity by positing dissociative pathology as fundamental to all cases, but Bleuler also referred to the group of schizophrenias. Throughout the 20th Century the reigning paradigm for schizophrenia has been the disease entity. The vast majority of studies use schizophrenia as the critical independent variable, and often use psychosis as broadly representing the disease entity. Two important challenges to the construct of schizophrenia as a disease entity are: 1) schizophrenia as a clinical syndrome comprising more than one disease entity; and 2) schizophrenia can be deconstructed into pathologic domains arising from separate disease processes.In this lecture, work related to each of these challenges is reviewed. Schizophrenia is deconstructed into pathologic domains with evidence for separateness at the level of onset, course, treatment response, pathophysiology and neuroanatomy. One domain, that of primary negative symptoms, is then used to identify a subroup of the schizophrenia syndrome. This subgroup
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PL.03. Plenary lecture
is distinguished from other cases of schizophrenia on clinical, biologic, and etiologic factors supporting the hypothesis of a distinct disease entity within the schizophrenia syndrome. Implications for future studies are profound. A shift to the domains of pathology paradigm give emphasis to novel therapeutic discovery. An emphasis on domains will facilitate the study of pathology across diagnostic classes, and will enable investigators to more closely link etiologic factors with pathology. References [1] Strauss JS, Carpenter Jr WT, Bartko JJ, 1974, The diagnosis and unerstanding of schizophrenia. Part III. Speculations on the processes that underlie schizophrenic symptoms and signs. Schizophr Bull 11(Winter), 61−69. [2] Kirkpatrick B, Buchanan RW, Ross DE, Carpenter WT, 2001, A separate disease within the syndrome of schizophrenia. Arch Gen Psychiatry 58, 165–171. [3] Carpenter WT, 2006, The schizophrenia paradigm: A hundred-year challenge (Editorial). J Nerv Mental Dis 195(9), 639–643.
Plenary lectures
PL.01. Plenary lecture PL.01 The endocannabinoids: functional roles and therapeutic opportunities R. Mechoulam ° . Hebrew University of Jerusalem, Faculty of Medicine, Jerusalem, Israel The major endocannabinoid, 2-arachidonoyl glycerol (2-AG) has been identified both in the central nervous system and in the periphery. Stressful stimuli – traumatic brain injury (TBI) for example – enhance brain 2-AG levels in mice. 2-AG, both of endogenous and exogenous origin, has been shown to be neuroprotective in closed head injury, ischemia and excitotoxicity in mice. These effects may derive from the ability of cannabinoids to act through various biochemical mechanisms, including inhibition of glutamate release or direct blockade of NMDA receptors, action as reactive oxygen species (ROS) scavengers, inhibition of proinflammatory cytokines and inhibition of NF-úB activation. 2-AG also helps repair the blood brain barrier after TBI. The endocannabinoids act via specific cannabinoid receptors, of which the CB1 receptors are most abundant in the CNS. We have shown that CB1 knockout mice display slower functional recovery after TBI and do not respond to treatment with 2-AG. Recently CB2 receptors have also been found to be formed in the brain, particularly in various pathological states. We assumed that the endocannabinoid system may be involved in the pathogenesis of hepatic encephalopathy, a neuropsychiatric syndrome induced by fulminant hepatic failure. Indeed in an animal model we found that brain levels of 2-AG are elevated. Administration of 2-AG or specific CB2 agonists improved neurological scores, activity and cognitive function. CB1 agonists were inactive. References [1] Mechoulam R, Panikashvili D, Shohami E, 2002, Cannabinoids and brain injury. Trends Mol Med 8, 58−61.
PL.02. ECNP Neuropsychopharmacology Award Lecture PL.02 Susceptibility or resilience to psychopathology? A question of stress, genes and balance E.R. De Kloet ° . Leiden University, Gorlaeus Laboratories Leiden/ Amsterdam Centre of Drug Research, Leiden, The Netherlands A fundamental question in the neuropsychopharmacology of affective disorders is how stress mediators that are crucial for health can change into harmful signals enhancing vulnerability to disease. To address this question I focus on cortisol. (1) Stress causes premature secretory bursts of cortisol, an adrenal hormone that is otherwise secreted in hourly pulses. The action of cortisol is mediated by mineralocorticoid (MR) and glucocorticoid receptors (GR) abundantly expressed in neurons
of hippocampus, amygdalae and frontal cortex. The receptors are transcription factors regulating gene transcription, but recently their rapid non-genomic action on glutamate transmission was discovered. MR participates in initial stress reactions important for appraisal and coping processes, while management of the later adaptive phase depends on GR. (2) Gene variants of MR and GR have been identified. The MR I180V variant shows loss of function and carriers display a strongly enhanced neuro-endocrine and autonomic responses to psychological stressors. Aged subjects carrying this polymorphism display prevalence of depressive symptoms suggesting the MR variant is a genetic risk factor. (3) Early life experience exerts through epigenomics lasting effects on MR/GR functioning underlying stress responsivity, cognitive performance and emotional arousal in later life. In conclusion, imbalance in stress mediators caused by genetic factors and early life experience is a characteristic feature of a vulnerable phenotype. This concept calls for recovery of the MR/GR balance as a therapeutic strategy to promote a mechanism of resilience still present in the diseased brain. Supported by KNAW and NWO. References [1] 2007, Nature Clin Endocrinol Metab 3, 168–179.
PL.03. Plenary lecture PL.03 The schizophrenia paradigm: a hundred-year challenge W.T. Carpenter Jr. ° . University of Maryland, Maryland Psychiatric Research Center, Baltimore, USA Kraepelin brought several putative diseases into the dementia praecox disease entity construct. Dissociative and avolitional pathology were described as the two primary clinical features arising from the same etiopathophysiology. Blueler reinforced the single disease entity by positing dissociative pathology as fundamental to all cases, but Bleuler also referred to the group of schizophrenias. Throughout the 20th Century the reigning paradigm for schizophrenia has been the disease entity. The vast majority of studies use schizophrenia as the critical independent variable, and often use psychosis as broadly representing the disease entity. Two important challenges to the construct of schizophrenia as a disease entity are: 1) schizophrenia as a clinical syndrome comprising more than one disease entity; and 2) schizophrenia can be deconstructed into pathologic domains arising from separate disease processes.In this lecture, work related to each of these challenges is reviewed. Schizophrenia is deconstructed into pathologic domains with evidence for separateness at the level of onset, course, treatment response, pathophysiology and neuroanatomy. One domain, that of primary negative symptoms, is then used to identify a subroup of the schizophrenia syndrome. This subgroup
S174
PL.03. Plenary lecture
is distinguished from other cases of schizophrenia on clinical, biologic, and etiologic factors supporting the hypothesis of a distinct disease entity within the schizophrenia syndrome. Implications for future studies are profound. A shift to the domains of pathology paradigm give emphasis to novel therapeutic discovery. An emphasis on domains will facilitate the study of pathology across diagnostic classes, and will enable investigators to more closely link etiologic factors with pathology. References [1] Strauss JS, Carpenter Jr WT, Bartko JJ, 1974, The diagnosis and unerstanding of schizophrenia. Part III. Speculations on the processes that underlie schizophrenic symptoms and signs. Schizophr Bull 11(Winter), 61−69. [2] Kirkpatrick B, Buchanan RW, Ross DE, Carpenter WT, 2001, A separate disease within the syndrome of schizophrenia. Arch Gen Psychiatry 58, 165–171. [3] Carpenter WT, 2006, The schizophrenia paradigm: A hundred-year challenge (Editorial). J Nerv Mental Dis 195(9), 639–643.