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Schizophrenia: an information processing disorder Cyril H schl

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Schizophrenia: an information processing disorder Cyril H schl

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    1. Höschl Schizophrenia: an information processing disorder Cyril Höschl

    2. Höschl Disclosure statement Höschl, 2007 In 2007, I was a paid consultant for: Lundbeck (LINF faculty member) Servier (research) Lectures for: Lilly BMS Other lectures exclusively for: Academia Medica Pragensis, Vienna School of Clinical Research, ECNP, AEP, universities and NGOs in EU.

    3. Höschl

    4. Höschl

    5. Höschl Pruning is one of crucial milestones in the development of the brain. Erroneous or excessive pruning (synaptic reduction in adolescence) could lead to disconnection as a basic neurodevelopmental impairment.Pruning is one of crucial milestones in the development of the brain. Erroneous or excessive pruning (synaptic reduction in adolescence) could lead to disconnection as a basic neurodevelopmental impairment.

    6. Höschl If pruning is modeled in neuronal network, it surprisingly lead at the beginning to the improvement of the function, i.e., correct computer-written reproduction of voice-recorded words, but further on the power declines. Moreover, after more than 40% synaptic reduction, the words are produced without any stimuli, just „from noise“, resembling spontaneous hallucinations. (Hoffmann and McGlashan, 1997)If pruning is modeled in neuronal network, it surprisingly lead at the beginning to the improvement of the function, i.e., correct computer-written reproduction of voice-recorded words, but further on the power declines. Moreover, after more than 40% synaptic reduction, the words are produced without any stimuli, just „from noise“, resembling spontaneous hallucinations. (Hoffmann and McGlashan, 1997)

    7. Höschl Cognitive function can be visualized. After neurocognitive task, the difference in regional activity of the tested brain and control person is recorded using for example fMRI or PET techniques.Cognitive function can be visualized. After neurocognitive task, the difference in regional activity of the tested brain and control person is recorded using for example fMRI or PET techniques.

    8. Höschl Brain imaging methods can visualize also auditory hallucinations. Increased activity is recorded in the right auditory temporo-parietal cortex and association left dorso-lateral prefrontal cortex.Brain imaging methods can visualize also auditory hallucinations. Increased activity is recorded in the right auditory temporo-parietal cortex and association left dorso-lateral prefrontal cortex.

    9. Höschl PET scans of the hallucinating patient rendered onto 3D brain models.PET scans of the hallucinating patient rendered onto 3D brain models.

    10. Höschl Supression both of the temporo-parietal metabolic activity and auditory hallucinations in chronic schizophrenic patient using inhibitory frequence of repetitive magnetic stimulation applied on T-P area (Prague Psychiatric Center).Supression both of the temporo-parietal metabolic activity and auditory hallucinations in chronic schizophrenic patient using inhibitory frequence of repetitive magnetic stimulation applied on T-P area (Prague Psychiatric Center).

    11. Höschl Disconnection in fronto-thalamo-cerebellar pathways can lead to cognitive dysmetria, which is the basis for cognitive impairment. This can lead to the development of psychotic symptoms.Disconnection in fronto-thalamo-cerebellar pathways can lead to cognitive dysmetria, which is the basis for cognitive impairment. This can lead to the development of psychotic symptoms.

    12. Höschl From the correspondence with Nancy Andreasen arguing the role of cerebellum in the pathogenesis of schizophrenic symptoms.From the correspondence with Nancy Andreasen arguing the role of cerebellum in the pathogenesis of schizophrenic symptoms.

    13. Höschl Another example of circuits, which can be dysfunctional in schizophrenia. Executive functions reverberate in „problem definition“ – „problem solving“ – „evaluation“.Another example of circuits, which can be dysfunctional in schizophrenia. Executive functions reverberate in „problem definition“ – „problem solving“ – „evaluation“.

    14. Höschl Principle of Stroop test The principle of Stroop test. If various signals processed together are incongruent, the highest control centers are employed, what represents a burden on executive functions, so that differences among subjects in different conditions can be assessed.The principle of Stroop test. If various signals processed together are incongruent, the highest control centers are employed, what represents a burden on executive functions, so that differences among subjects in different conditions can be assessed.

    15. Höschl Nobel Prize Winner Arvid Carlsson is an author of schematic map of psychotogenic pathways in the brain. Nobel Prize Winner Arvid Carlsson is an author of schematic map of psychotogenic pathways in the brain.

    16. Höschl Potential psychotogenic pathways The map shows various excitatory or inhibitory influences on striato-thalamic GABAergic gating system. Impaired gating leads to flooding of the cortex with stimuli (noise), which can not be properly processed. The schema partly explains pharmacological models of schizophrenia-like psychoses (e.g., amphetamine, phencyclidine /PCP/, LSD, atropine, etc.) as well as dopaminergic or glutamatergic hypothesis of schizophrenia. Most of the relevant sites of the map (D2, 5-HT and NMDA receptors) play important role in the mode of action of antipsychotic drugs.The map shows various excitatory or inhibitory influences on striato-thalamic GABAergic gating system. Impaired gating leads to flooding of the cortex with stimuli (noise), which can not be properly processed. The schema partly explains pharmacological models of schizophrenia-like psychoses (e.g., amphetamine, phencyclidine /PCP/, LSD, atropine, etc.) as well as dopaminergic or glutamatergic hypothesis of schizophrenia. Most of the relevant sites of the map (D2, 5-HT and NMDA receptors) play important role in the mode of action of antipsychotic drugs.

    17. Höschl Potential psychotogenic pathways „Neurochemical“ map of psychotogenic pathways in the brain.„Neurochemical“ map of psychotogenic pathways in the brain.

    18. Höschl Serotonin-Dopamine Interaction In schizophrenia, there is a dopaminergic dysballance rather than excess or lack of dopamine. While in mesolimbic areas the dopaminergic activity is inreased, there might be a decrease in prefrontal cortex, particularly in relation to negative symptoms. The limbic connection to prefrontal cortex (PFC) is under serotonergic inhibitory control via 5-HT2 receptors. This may be the reason why atypical antipsychotics antagonizing besides D2 also 5-HT2 receptors can improve also negative symptoms (type II schizophrenia) while preserving antipsychotic efficacy in type I.In schizophrenia, there is a dopaminergic dysballance rather than excess or lack of dopamine. While in mesolimbic areas the dopaminergic activity is inreased, there might be a decrease in prefrontal cortex, particularly in relation to negative symptoms. The limbic connection to prefrontal cortex (PFC) is under serotonergic inhibitory control via 5-HT2 receptors. This may be the reason why atypical antipsychotics antagonizing besides D2 also 5-HT2 receptors can improve also negative symptoms (type II schizophrenia) while preserving antipsychotic efficacy in type I.

    19. Höschl The main mode of action of antipsychotic drugs in D2R antagonism. This is shared by almost all of antipsychotic drugs.The main mode of action of antipsychotic drugs in D2R antagonism. This is shared by almost all of antipsychotic drugs.

    20. Höschl D2 antagonism leads not only to favourable clinical effect, but also to unpleasant and harmful side effects like extrapyramidal symptoms (EPS, parkinsonism) and prolactin elevation. To reduce the risk of EPS, classical compounds exert also some anti-muscarinic activity. It leads, however, to further (anticholinergic) side-effects. Other side-effects occur due to affinity to different types of receptors, e.g., histaminic, alpha-adrenergic, etc.D2 antagonism leads not only to favourable clinical effect, but also to unpleasant and harmful side effects like extrapyramidal symptoms (EPS, parkinsonism) and prolactin elevation. To reduce the risk of EPS, classical compounds exert also some anti-muscarinic activity. It leads, however, to further (anticholinergic) side-effects. Other side-effects occur due to affinity to different types of receptors, e.g., histaminic, alpha-adrenergic, etc.

    21. Höschl Receptor affinity can be tested also in man in vivo. Shitij Kapur from Toronto suggested D2 occupancy as a crucial factor in developing antipsychotic (more than 60%) and/or extrapyramidal (more than 70%) effects. Novel antipsychotics exert in addition also anti-serotonergic efficacy, which can enlarge the therapeutic window between antipsychoatic and cataleptic doses. Receptor affinity profile of novel antipsychotics can also serve as a classification criterion for this group (Svestka 2002)Receptor affinity can be tested also in man in vivo. Shitij Kapur from Toronto suggested D2 occupancy as a crucial factor in developing antipsychotic (more than 60%) and/or extrapyramidal (more than 70%) effects. Novel antipsychotics exert in addition also anti-serotonergic efficacy, which can enlarge the therapeutic window between antipsychoatic and cataleptic doses. Receptor affinity profile of novel antipsychotics can also serve as a classification criterion for this group (Svestka 2002)

    22. Höschl The role of serotonin blockade in mechanism of action of novel antipsychotics can be tested in animal models. The movement trajectory of a rat in open field can be video-recorded and processed (see above). Various parameters of the trajectory can be followed in different conditions, e.g., in control (water/saline), „psychotic“ (NMDA antagonist MK801), haloperidol-treated „psychotic“ (water/hal/MK801), and tryptophan depleted, haloperidol treated „psychotic“ (Trp-/hal/MK801) animals. The trajectory of the last animal resembles most the normal conditions. Tryptophan depletion simulates in this model „anti-serotonergic“ property of novel antipsychotics. (Horácek et al.2003)The role of serotonin blockade in mechanism of action of novel antipsychotics can be tested in animal models. The movement trajectory of a rat in open field can be video-recorded and processed (see above). Various parameters of the trajectory can be followed in different conditions, e.g., in control (water/saline), „psychotic“ (NMDA antagonist MK801), haloperidol-treated „psychotic“ (water/hal/MK801), and tryptophan depleted, haloperidol treated „psychotic“ (Trp-/hal/MK801) animals. The trajectory of the last animal resembles most the normal conditions. Tryptophan depletion simulates in this model „anti-serotonergic“ property of novel antipsychotics. (Horácek et al.2003)

    23. Höschl DAAO=D-amino acid oxydaseDAAO=D-amino acid oxydase

    24. Höschl DAAO=D-amino acid oxydaseDAAO=D-amino acid oxydase

    25. Höschl DAAO=D-amino acid oxydaseDAAO=D-amino acid oxydase

    26. Höschl

    27. Höschl Mechanisms of action of SGA Trk receptors are a family of three receptor tyrosine kinases, each of which can be activated by one or more of four neurotrophins nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophins 3 and 4 (NT3 and NT4). Neurotrophin signaling through these receptors regulates cell survival, proliferation, the fate of neural precursors, axon and dendrite growth and patterning, and the expression and activity of functionally important proteins, such as ion channels and neurotransmitter receptors. In the adult nervous system, the Trk receptors regulate synaptic strength and plasticity. The cytoplasmic domains of Trk receptors contain several sites of tyrosine phosphorylation that recruit intermediates in intracellular signaling cascades. As a result, Trk receptor signaling activates several small G proteins, including Ras, Rap-1, and the Cdc-42-Rac-Rho family, as well as pathways regulated by MAP kinase, PI 3-kinase and phospholipase-C- (PLC- ). Trk receptor activation has different consequences in different cells, and the specificity of downstream Trk receptor-mediated signaling is controlled through expression of intermediates in these signaling pathways and membrane trafficking that regulates localization of different signaling constituents. Perhaps the most fascinating aspect of Trk receptor-mediated signaling is its interplay with signaling promoted by the pan-neurotrophin receptor p75NTR. p75NTR activates a distinct set of signaling pathways within cells that are in some instances synergistic and in other instances antagonistic to those activated by Trk receptors. Several of these are proapoptotic but are suppressed by Trk receptor-initiated signaling. p75NTR also influences the conformations of Trk receptors; this modifies ligand-binding specificity and affinity with important developmental consequences. Annual Review of Biochemistry Vol. 72: 609-642 (Volume publication date July 2003) TRK RECEPTORS: ROLES IN NEURONAL SIGNAL TRANSDUCTION * Eric J. Huang and Louis F. Reichardt Trk receptors are a family of three receptor tyrosine kinases, each of which can be activated by one or more of four neurotrophins nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophins 3 and 4 (NT3 and NT4). Neurotrophin signaling through these receptors regulates cell survival, proliferation, the fate of neural precursors, axon and dendrite growth and patterning, and the expression and activity of functionally important proteins, such as ion channels and neurotransmitter receptors. In the adult nervous system, the Trk receptors regulate synaptic strength and plasticity. The cytoplasmic domains of Trk receptors contain several sites of tyrosine phosphorylation that recruit intermediates in intracellular signaling cascades. As a result, Trk receptor signaling activates several small G proteins, including Ras, Rap-1, and the Cdc-42-Rac-Rho family, as well as pathways regulated by MAP kinase, PI 3-kinase and phospholipase-C- (PLC- ). Trk receptor activation has different consequences in different cells, and the specificity of downstream Trk receptor-mediated signaling is controlled through expression of intermediates in these signaling pathways and membrane trafficking that regulates localization of different signaling constituents. Perhaps the most fascinating aspect of Trk receptor-mediated signaling is its interplay with signaling promoted by the pan-neurotrophin receptor p75NTR. p75NTR activates a distinct set of signaling pathways within cells that are in some instances synergistic and in other instances antagonistic to those activated by Trk receptors. Several of these are proapoptotic but are suppressed by Trk receptor-initiated signaling. p75NTR also influences the conformations of Trk receptors; this modifies ligand-binding specificity and affinity with important developmental consequences. Annual Review of BiochemistryVol. 72: 609-642 (Volume publication date July 2003) TRK RECEPTORS: ROLES IN NEURONAL SIGNAL TRANSDUCTION * Eric J. Huang and Louis F. Reichardt

    28. Höschl Mechanisms of action of SGA Wang HD, Dunnavant FD, Jarman T, Deutch AY. Effects of antipsychotic drugs on neurogenesis in the forebrain of the adult rat. Neuropsychopharmacology. 2004 Jul;29(7):1230-8. Departments of Psychiatry and Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37212, USA. huidong.wang@vanderbilt.edu The generation of new cells in the adult mammalian brain may significantly modify pathophysiological processes in neuropsychiatric disorders. We examined the ability of chronic treatment with the antipsychotic drugs (APDs) olanzapine and haloperidol to increase the number and survival of newly generated cells in the prefrontal cortex (PFC) and striatal complex of adult male rats. Animals were treated with olanzapine or haloperidol for 3 weeks and then injected with 5-bromo-2'-deoxyuridine (BrdU) to label mitotic cells. Half of the animals continued on the same APD for two more weeks after BrdU challenge, with the other half receiving vehicle during this period. Olanzapine but not haloperidol significantly increased both the total number and density of BrdU-labeled cells in the PFC and dorsal striatum; no effect was observed in the nucleus accumbens. Continued olanzapine treatment after the BrdU challenge did not increase the survival of newly generated cells. The newly generated cells in the PFC did not express the neuronal marker NeuN. Despite the significant increase in newly generated cells in the PFC of olanzapine-treated rats, the total number of these cells is low, suggesting that the therapeutic effects of atypical APD treatment may not be due to the presence of newly generated cells that have migrated to the cortex. Wang HD, Dunnavant FD, Jarman T, Deutch AY. Effects of antipsychotic drugs on neurogenesis in the forebrain of the adult rat. Neuropsychopharmacology. 2004 Jul;29(7):1230-8. Departments of Psychiatry and Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37212, USA. huidong.wang@vanderbilt.eduThe generation of new cells in the adult mammalian brain may significantly modify pathophysiological processes in neuropsychiatric disorders. We examined the ability of chronic treatment with the antipsychotic drugs (APDs) olanzapine and haloperidol to increase the number and survival of newly generated cells in the prefrontal cortex (PFC) and striatal complex of adult male rats. Animals were treated with olanzapine or haloperidol for 3 weeks and then injected with 5-bromo-2'-deoxyuridine (BrdU) to label mitotic cells. Half of the animals continued on the same APD for two more weeks after BrdU challenge, with the other half receiving vehicle during this period. Olanzapine but not haloperidol significantly increased both the total number and density of BrdU-labeled cells in the PFC and dorsal striatum; no effect was observed in the nucleus accumbens. Continued olanzapine treatment after the BrdU challenge did not increase the survival of newly generated cells. The newly generated cells in the PFC did not express the neuronal marker NeuN. Despite the significant increase in newly generated cells in the PFC of olanzapine-treated rats, the total number of these cells is low, suggesting that the therapeutic effects of atypical APD treatment may not be due to the presence of newly generated cells that have migrated to the cortex.

    29. Höschl Mechanisms of action of SGA Wang HD, Dunnavant FD, Jarman T, Deutch AY. Effects of antipsychotic drugs on neurogenesis in the forebrain of the adult rat. Neuropsychopharmacology. 2004 Jul;29(7):1230-8. Departments of Psychiatry and Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37212, USA. huidong.wang@vanderbilt.edu The generation of new cells in the adult mammalian brain may significantly modify pathophysiological processes in neuropsychiatric disorders. We examined the ability of chronic treatment with the antipsychotic drugs (APDs) olanzapine and haloperidol to increase the number and survival of newly generated cells in the prefrontal cortex (PFC) and striatal complex of adult male rats. Animals were treated with olanzapine or haloperidol for 3 weeks and then injected with 5-bromo-2'-deoxyuridine (BrdU) to label mitotic cells. Half of the animals continued on the same APD for two more weeks after BrdU challenge, with the other half receiving vehicle during this period. Olanzapine but not haloperidol significantly increased both the total number and density of BrdU-labeled cells in the PFC and dorsal striatum; no effect was observed in the nucleus accumbens. Continued olanzapine treatment after the BrdU challenge did not increase the survival of newly generated cells. The newly generated cells in the PFC did not express the neuronal marker NeuN. Despite the significant increase in newly generated cells in the PFC of olanzapine-treated rats, the total number of these cells is low, suggesting that the therapeutic effects of atypical APD treatment may not be due to the presence of newly generated cells that have migrated to the cortex. Wang HD, Dunnavant FD, Jarman T, Deutch AY. Effects of antipsychotic drugs on neurogenesis in the forebrain of the adult rat. Neuropsychopharmacology. 2004 Jul;29(7):1230-8. Departments of Psychiatry and Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37212, USA. huidong.wang@vanderbilt.eduThe generation of new cells in the adult mammalian brain may significantly modify pathophysiological processes in neuropsychiatric disorders. We examined the ability of chronic treatment with the antipsychotic drugs (APDs) olanzapine and haloperidol to increase the number and survival of newly generated cells in the prefrontal cortex (PFC) and striatal complex of adult male rats. Animals were treated with olanzapine or haloperidol for 3 weeks and then injected with 5-bromo-2'-deoxyuridine (BrdU) to label mitotic cells. Half of the animals continued on the same APD for two more weeks after BrdU challenge, with the other half receiving vehicle during this period. Olanzapine but not haloperidol significantly increased both the total number and density of BrdU-labeled cells in the PFC and dorsal striatum; no effect was observed in the nucleus accumbens. Continued olanzapine treatment after the BrdU challenge did not increase the survival of newly generated cells. The newly generated cells in the PFC did not express the neuronal marker NeuN. Despite the significant increase in newly generated cells in the PFC of olanzapine-treated rats, the total number of these cells is low, suggesting that the therapeutic effects of atypical APD treatment may not be due to the presence of newly generated cells that have migrated to the cortex.

    30. Höschl Summary 1/3 Antipsychotics predominantly block D2R It leads to side effects and lack of efficacy in negative and depressi-ve symptoms of psychoses In addition, SGA block 5HT2, what improves negative symptoms Aripiprazole does not just block, but stabilizes D2 (partial agonist) Some SGA agonize 5HT1A 5-HT1A R plays important role in the regulation of mood 5-HT1A R is necessary for neurogenesis

    31. Höschl Summary 2/3 SGA? ? BDNF expression and so bcl2 as well SGA block GSK-3ß phospho-rylation and thus ? apoptosis Neuroprotective SGA effects in SCH counteract decline of grey matter, compared to FGA (Lieberman et al. 2004) Relationship to cognitive functions remains unclear

    32. Höschl Summary 3/3

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