Behavioral Neurobiology of Schizophrenia and Its Treatment

1. Auflage 2010
ISBN: 978-3-642-13717-4
Verlag: Springer
Format: PDF
Kopierschutz: Adobe DRM (»Systemvoraussetzungen)

E-Book, Englisch, 666 Seiten

This book describes the state-of-the-art of treatment of schizophrenia and reflects its development in 22 chapters written by leading authorities in the field

Autoren/Hrsg.

Inhaltsverzeichnis

1;Preface;6
2;Contents;10
3;Contributors;14
4;Part I: Function, Outcome and Treatmentin Schizophrenia;20
4.1;Assessing Function and Functional Outcome in Schizophrenia;21
4.1.1;1 Introduction;22
4.1.1.1;1.1 Functional Dimensions;22
4.1.1.2;1.2 Recent Reviews and Overviews of Measures of Functioning in Schizophrenia;24
4.1.2;2 Construct Validity;25
4.1.2.1;2.1 Functional Outcome as an Experiential Process;26
4.1.2.2;2.2 Environmental Moderators of the Functional Dimensions;28
4.1.3;3 Ecological Validity;29
4.1.3.1;3.1 Verisimilitude and Veridicality;30
4.1.3.2;3.2 Observation in Naturalistic Environments;32
4.1.4;4 Conclusion;34
4.1.5;References;34
4.2;Antipsychotics and Metabolics in the Post-CATIE Era;40
4.2.1;1 Introduction;41
4.2.2;2 Sources of Cardiovascular Risk;43
4.2.3;3 The Cardiovascular and Metabolic Risk Profile of Subjects Entering the CATIE Schizophrenia Trial;46
4.2.4;4 The Impact of Antipsychotic Treatment on Cardiovascular and Metabolic Outcomes in the CATIE Schizophrenia Trial;47
4.2.4.1;4.1 Metabolic Outcomes;47
4.2.4.2;4.2 Framingham Cardiovascular Risk;48
4.2.4.3;4.3 Outcomes with Novel Biomarkers;50
4.2.5;5 The Post-CATIE Era;50
4.2.5.1;5.1 Clinical Conclusions;50
4.2.5.2;5.2 Hypotheses on Schizophrenia and Metabolic Risk, and Adiposity-Independent Drug Effects;52
4.2.6;6 Conclusions;54
4.2.7;References;54
4.3;Pharmacological Strategies for Enhancing Cognition in Schizophrenia;60
4.3.1;1 Introduction;61
4.3.2;2 Cholinergic Agents;63
4.3.2.1;2.1 Cholinesterase Inhibitors;64
4.3.2.2;2.2 Nicotine, Nicotinic Receptor Agonists, and Muscarinic Receptor Agonists;68
4.3.3;3 Glutamatergic Agents;77
4.3.3.1;3.1 Glycine Allosteric Modulators;77
4.3.3.2;3.2 AMPA Receptor Modulators;78
4.3.3.3;3.3 Phosphodiesterase 5 Inhibitors;83
4.3.3.4;3.4 NMDA Receptor Antagonists;83
4.3.4;4 Gamma-Aminobutyric Acid Modulating Agents;84
4.3.5;5 Dopaminergic Agents;87
4.3.5.1;5.1 Indirect Dopamine Agonists;88
4.3.5.2;5.2 Atomoxetine and Amantadine;88
4.3.5.3;5.3 Selective Dopamine Agonists;93
4.3.6;6 Modafinil;94
4.3.7;7 Other Agents;97
4.3.8;8 Conclusions;100
4.3.9;References;102
4.4;Treatment Implications of the Schizophrenia Prodrome;114
4.4.1;1 Introduction;115
4.4.1.1;1.1 Early Identification of Psychotic Illness;117
4.4.1.2;1.2 Duration of Untreated Psychosis: Individual and Public Health Concern;117
4.4.1.3;1.3 Identifying and Predicting Risk for Psychotic Illnesses;118
4.4.1.4;1.4 Review of Treatment Studies in the Psychotic Prodrome;121
4.4.1.5;1.5 Nonpharmacologic Interventions;122
4.4.1.6;1.6 Psychopharmacologic Interventions;123
4.4.1.7;1.7 Pharmacologic Potential for Neuroprotection;124
4.4.1.8;1.8 Preliminary Treatment Recommendations;126
4.4.1.9;1.9 Ethical Implications;126
4.4.1.10;1.10 Development of Clinical Staging Criteria;128
4.4.1.11;1.11 Recommended Treatment Guidelines;129
4.4.1.12;1.12 General Summary;132
4.4.2;References;132
4.5;Antipsychotic Drug Development;139
4.5.1;1 Introduction;140
4.5.2;2 Dopamine D2 Receptors: Antagonism, Inverse Agonism, and Partial Agonism;141
4.5.3;3 Dopamine D3 Receptors: Cognition and ``Optimized Antagonism´´ at D3 Versus D2 Receptors;145
4.5.4;4 Serotonin 5-HT2A Receptors: Dopamine Brakes;146
4.5.5;5 Serotonin 5-HT1A Receptors: Dopamine Accelerators;146
4.5.6;6 Serotonin 5-HT2C Receptors;147
4.5.7;7 Serotonin 5-HT7 Receptors;148
4.5.8;8 Glutamatergic Receptors: NMDA and mGluR;148
4.5.9;9 Glycine Agonists;150
4.5.10;10 Receptors That Mediate Side Effects;150
4.5.11;11 Conclusion;151
4.5.12;References;151
4.6;Antipsychotic Dosing and Drug Delivery;156
4.6.1;1 Background;157
4.6.2;2 History;158
4.6.3;3 Dopamine Hypothesis;158
4.6.4;4 D2 Mechanism of Antipsychotic Medication;159
4.6.5;5 Clozapine;160
4.6.6;6 Genesis and Interpretation of ``Atypicality´´;160
4.6.7;7 Current State of Affairs;161
4.6.8;8 Dosing;161
4.6.8.1;8.1 Chlorpromazine Equivalents;161
4.6.8.2;8.2 Other Contributions (Non-D2) to Efficacy;164
4.6.8.2.1;8.2.1 Potential Benefits of Continuous Infusion;166
4.6.8.2.2;8.2.2 Alternative Hypothesis;167
4.6.9;9 Adherence;168
4.6.9.1;9.1 Background and Clinical Perspective;168
4.6.9.1.1;9.1.1 Adherence Rates;168
4.6.9.1.2;9.1.2 Relapse Rates as a Function of Adherence;168
4.6.9.1.3;9.1.3 Causes of Poor Adherence;169
4.6.9.2;9.2 Development of Depots;169
4.6.9.2.1;9.2.1 Clinical Studies and Meta-Analyses Comparing Depots to Oral Administration;169
4.6.9.2.2;9.2.2 Barriers to Creating Depots for More Agents;170
4.6.9.3;9.3 Development of Polymer-Based Microsphere Systems to Overcome Limitations of Chemistry;170
4.6.9.4;9.4 Potential Extension to Implants;171
4.6.9.4.1;9.4.1 Biodegradable Versus Nonbiodegradable;171
4.6.9.4.1.1;Nondegradable;171
4.6.9.4.1.2;Biodegradable Systems;172
4.6.9.4.2;9.4.2 PLGA/PLA;172
4.6.9.4.3;9.4.3 Poly(epsi-Caprolactone);173
4.6.9.4.4;9.4.4 Drug Release Mechanisms;174
4.6.9.4.5;9.4.5 Erosion;174
4.6.9.4.6;9.4.6 Diffusion;175
4.6.9.4.7;9.4.7 Advantages;176
4.6.9.4.7.1;Duration;176
4.6.9.4.7.2;Reversibility;177
4.6.9.4.8;9.4.8 Limitations;178
4.6.9.4.8.1;Physical Drug Characteristics;178
4.6.9.4.8.1.1;Stability of the Molecule in a Physiological Environment;178
4.6.9.4.8.1.2;Ethical Considerations;179
4.6.9.4.8.1.3;Extension to Other Areas;180
4.6.9.5;9.5 Transdermal Delivery Systems;180
4.6.9.5.1;9.5.1 Potential Benefits;180
4.6.9.5.2;9.5.2 Passive Systems;182
4.6.9.5.3;9.5.3 Active Iontophoretic Systems;182
4.6.9.5.4;9.5.4 Limitations;183
4.6.9.6;9.6 Barriers to Development of Novel Delivery Systems;183
4.6.9.6.1;9.6.1 Long Clinical Trial Length;183
4.6.9.6.2;9.6.2 Inclusion of Controls in Studies of 6-Month Exposure to Antipsychotic Medications;184
4.6.9.6.3;9.6.3 Placebo Arm in Patients for Length of Time Needed to Truly Test a 6-Month Delivery System;184
4.6.10;10 Summary and Conclusions;185
4.6.11;References;185
5;Part II: Experimental measures of brain functionand dysfunction in schizophenia;193
5.1;Functional Brain Imaging in Schizophrenia: Selected Results and Methods;194
5.1.1;1 Introduction;195
5.1.2;2 Critical Regions;196
5.1.2.1;2.1 Positive Symptoms;197
5.1.2.1.1;2.1.1 Spontaneous Presentation;198
5.1.2.1.2;2.1.2 Brain Activation Studies;202
5.1.2.1.3;2.1.3 Comments;203
5.1.2.2;2.2 Negative Symptoms;203
5.1.2.2.1;2.2.1 Studies of Uncontrolled Mental State;204
5.1.2.2.2;2.2.2 Studies of Brain Activation: Working Memory;206
5.1.2.2.3;2.2.3 Summary and Comments;211
5.1.3;3 Brain Systems;212
5.1.3.1;3.1 Functional Connectivity;212
5.1.3.2;3.2 Summary and Comments;218
5.1.4;4 Final Comments and Emerging Trends;219
5.1.5;References;220
5.2;Neurochemical Imaging in Schizophrenia;228
5.2.1;1 Introduction;229
5.2.2;2 Brief Overview of Neurochemical Imaging Techniques;230
5.2.3;3 Imaging Neurotransmitter Systems;232
5.2.3.1;3.1 Dopamine;232
5.2.3.1.1;3.1.1 Striatal DA Parameters;232
5.2.3.1.1.1;D2 Receptors;232
5.2.3.1.1.1.1;Baseline Striatal D2 Receptor Density;232
5.2.3.1.1.1.2;DA Release: Pharmacological Challenge Studies;234
5.2.3.1.1.1.3;Baseline DA Release;234
5.2.3.1.1.2;Striatal D1 Receptors;235
5.2.3.1.1.3;Dopamine Transporters;235
5.2.3.1.1.4;DA Synthesis;236
5.2.3.1.2;3.1.2 Extrastriatal Dopamine;237
5.2.3.1.2.1;D2 Receptors;237
5.2.3.1.2.2;Extrastriatal D1 Receptors;237
5.2.3.2;3.2 Serotonin;238
5.2.3.2.1;3.2.1 5-HT2A Receptors;239
5.2.3.2.2;3.2.2 5-HT1A Receptors;239
5.2.3.2.3;3.2.3 Serotonin Transporters;240
5.2.3.3;3.3 Gamma-Aminobutyric Acid;240
5.2.3.4;3.4 N-Methyl-d-Aspartic Acid and Glutamate;241
5.2.4;4 Occupancy Studies (Pharmacological Studies);241
5.2.4.1;4.1 DA Receptor Occupancy;242
5.2.4.1.1;4.1.1 D2 Receptor Occupancy;242
5.2.4.1.1.1;Implications for Treatment;242
5.2.4.1.2;4.1.2 D1 Receptor Occupancy;244
5.2.4.2;4.2 Serotonin Occupancy;244
5.2.4.2.1;4.2.1 5-HT2A Receptor Occupancy;244
5.2.4.2.2;4.2.2 5-HT1A Receptor Occupancy;245
5.2.5;5 Future Directions;245
5.2.6;References;246
5.3;A Selective Review of Volumetric and Morphometric Imaging in Schizophrenia;256
5.3.1;1 Introduction;257
5.3.2;2 Limbic/Paralimbic Regions;258
5.3.3;3 Prefrontal Cortical Regions;269
5.3.4;4 Caudate Nucleus;277
5.3.5;5 Neocortical Temporal Lobe;281
5.3.6;6 Conclusion;289
5.3.7;References;290
5.4;Neurophysiological Measures of Sensory Registration, Stimulus Discrimination, and Selection in Schizophrenia Patients;295
5.4.1;1 Introduction;296
5.4.1.1;1.1 Automatic and Attention Dependent Processes;297
5.4.1.2;1.2 Event-Related Potentials;298
5.4.1.3;1.3 The Oddball Paradigm;299
5.4.1.4;1.4 Basic Processes;301
5.4.2;2 N1 ERP;302
5.4.2.1;2.1 N1 Deficits in Schizophrenia;303
5.4.2.2;2.2 N1 Stability, Reliability, and Heritability;304
5.4.3;3 MMN ERP;305
5.4.3.1;3.1 MMN Deficits in Schizophrenia;306
5.4.3.2;3.2 MMN Stability, Reliability, and Heritability;308
5.4.4;4 P300 ERP;309
5.4.4.1;4.1 P300 Deficits in Schizophrenia;310
5.4.4.2;4.2 P3 Stability, Reliability, and Heritability;311
5.4.5;5 Discussion;312
5.4.6;References;313
5.5;Eye Tracking Dysfunction in Schizophrenia: Characterization and Pathophysiology;322
5.5.1;1 Introduction;323
5.5.2;2 Components of the Smooth Pursuit Eye Tracking Response;326
5.5.3;3 Characterization of ETD;329
5.5.4;4 Pathophysiology of ETD;333
5.5.4.1;4.1 Behavioral Evaluations of the Contribution of Motion Processing to ETD;333
5.5.4.1.1;4.1.1 Psychophysical Judgment Studies of Motion Perception;334
5.5.4.1.2;4.1.2 Saccadic Studies of Motion Perception;341
5.5.4.1.3;4.1.3 Pursuit Initiation Studies;341
5.5.4.2;4.2 Extraretinal Processes in Pursuit;342
5.5.4.3;4.3 Neuroimaging of Pursuit and Component Processes;345
5.5.5;5 Association Between Genetic Polymorphisms and ETD;347
5.5.6;6 Summary;348
5.5.7;References;348
5.6;Prepulse Inhibition of the Startle Reflex: A Window on the Brain in Schizophrenia;359
5.6.1;1 Background of PPI Studies;360
5.6.2;2 Prepulse Inhibition Deficits in Schizophrenia Spectrum (and Other) Patients;363
5.6.3;3 Sex, Symptoms, Cognitive, and Functional Correlates of PPI Deficits in Schizophrenia Patients;365
5.6.4;4 Pharmacological Studies of PPI in Human Subjects Relevant to Schizophrenia;365
5.6.4.1;4.1 Dopamine;366
5.6.4.2;4.2 Nicotine;367
5.6.5;5 Antipsychotic Medications in Schizophrenia Patients;368
5.6.6;6 Genomic Influences on PPI in Schizophrenia;369
5.6.7;7 Summary and Future Directions;373
5.6.8;References;375
5.7;Neurocognition in Schizophrenia;382
5.7.1;1 Introduction;383
5.7.2;2 General Intellectual Functioning;384
5.7.3;3 Attention;385
5.7.4;4 Processing Speed;386
5.7.5;5 Executive Functioning;386
5.7.6;6 Learning and Memory;388
5.7.7;7 Language;389
5.7.8;8 Visual Perceptual/Constructional Skills;390
5.7.9;9 Fine Motor Skills;390
5.7.10;10 Social Cognition;391
5.7.11;11 Deficits Among Populations at Risk and Endophenotypes;392
5.7.12;12 Longitudinal Studies of Neuropsychological Deficits;393
5.7.13;13 Future Directions of Research;394
5.7.14;References;395
5.8;Animal Models of Schizophrenia;400
5.8.1;1 Introduction;401
5.8.2;2 Criteria Used to Validate Animal Models;404
5.8.2.1;2.1 Reliability;404
5.8.2.2;2.2 Face Validity;405
5.8.2.3;2.3 Predictive Validity;405
5.8.2.4;2.4 Construct Validity;405
5.8.2.5;2.5 Etiological Validity;406
5.8.3;3 Modeling Schizophrenia in Animals;406
5.8.4;4 Behavioral Measures by Symptom Group;407
5.8.4.1;4.1 Positive Symptoms;407
5.8.4.2;4.2 Negative Symptoms;408
5.8.4.2.1;4.2.1 Progressive Ratio Breakpoint Studies;408
5.8.4.2.2;4.2.2 Intracranial Self-Stimulation;409
5.8.4.3;4.3 Cognitive Symptoms;409
5.8.4.3.1;4.3.1 Attentional Dysfunction;410
5.8.4.3.1.1;5-Choice Serial Reaction-Time Task;410
5.8.4.3.1.2;Sustained Attention Task;410
5.8.4.3.2;4.3.2 Executive Function;410
5.8.4.3.2.1;Attentional Set-Shifting Task;410
5.8.4.3.3;4.3.3 Working Memory;411
5.8.4.3.3.1;Radial Arm Maze;411
5.8.4.3.3.2;Odor Span Task;411
5.8.4.3.4;4.3.4 Visual Learning and Memory;412
5.8.4.3.4.1;Morris Water Maze;412
5.8.4.3.4.2;Novel Object Recognition Task;412
5.8.4.4;4.4 Sensorimotor Gating Paradigms;412
5.8.4.4.1;4.4.1 Prepulse Inhibition;412
5.8.4.4.2;4.4.2 Auditory Gating;413
5.8.4.5;4.5 Latent Inhibition;413
5.8.5;5 Experimental Manipulations for Animal Models of Schizophrenia;414
5.8.5.1;5.1 Dopaminergic Agonist Models;414
5.8.5.1.1;5.1.1 Acute Models;415
5.8.5.1.2;5.1.2 Repeat Administration Models;415
5.8.5.2;5.2 Glutamatergic Antagonist Models;416
5.8.5.2.1;5.2.1 Acute Models;417
5.8.5.2.2;5.2.2 Repeated Dosing Models;417
5.8.5.3;5.3 Serotonergic Agonist Models;418
5.8.5.4;5.4 Cholinergic Antagonist Models;419
5.8.5.5;5.5 Lesion Models;420
5.8.5.6;5.6 Genetic Models for Schizophrenia;421
5.8.5.6.1;5.6.1 Schizophrenia as a Genetic Disease;421
5.8.5.6.2;5.6.2 Candidate Susceptibility Genes for Schizophrenia;421
5.8.5.6.2.1;Human Genetic Linkage and Association;422
5.8.5.6.2.1.1;Neuregulin-1;422
5.8.5.6.2.1.2;Dysbindin;422
5.8.5.6.2.2;Cytogenetic Studies;423
5.8.5.6.2.2.1;Disrupted in Schizophrenia 1;423
5.8.5.6.2.2.2;COMT;423
5.8.5.6.2.2.3;NPAS3;424
5.8.5.7;5.7 Candidate Genes from Animal Models;424
5.8.5.7.1;5.7.1 Sp4;424
5.8.5.7.2;5.7.2 Copy Number Variation;424
5.8.5.7.3;5.7.3 Chromosome 22q11 Deletion;425
5.8.5.7.4;5.7.4 Chromosome 15q13.3 Deletion;425
5.8.5.8;5.8 Transgenic Mouse Models;425
5.8.5.8.1;5.8.1 Neuregulin;425
5.8.5.8.2;5.8.2 Dysbindin;426
5.8.5.8.3;5.8.3 DISC1;426
5.8.5.8.4;5.8.4 COMT;427
5.8.5.8.5;5.8.5 CHRNA7;428
5.8.6;6 Conclusions;428
5.8.7;References;429
5.9;Models of Neurodevelopmental Abnormalities in Schizophrenia;443
5.9.1;1 Neurodevelopmental Models of Schizophrenia;445
5.9.1.1;1.1 Developmental Theory of Schizophrenia;445
5.9.1.2;1.2 Animal Models of Developmental Hypothesis;446
5.9.2;2 Behavioral Measures;447
5.9.2.1;2.1 Spontaneous and Drug-Induced Locomotor Activity;448
5.9.2.2;2.2 Gating Deficits;448
5.9.2.3;2.3 Attention;449
5.9.2.4;2.4 Cognitive Deficits;449
5.9.2.5;2.5 Social Interaction;450
5.9.3;3 Epidemiologic-Based Developmental Manipulations;450
5.9.3.1;3.1 Viral and Immune-Activating Models of Schizophrenia;451
5.9.3.1.1;3.1.1 Prenatal Viral Exposure;453
5.9.3.1.2;3.1.2 Prenatal PolyI:C Exposure;453
5.9.3.1.3;3.1.3 Prenatal LPS Exposure;454
5.9.3.1.4;3.1.4 Role of Cytokines in Prenatal Immune Models;455
5.9.3.1.5;3.1.5 Neonatal Immune Activation;455
5.9.3.1.6;3.1.6 Discussion of Immune Models;456
5.9.3.2;3.2 Maternal Malnutrition;456
5.9.3.2.1;3.2.1 Prenatal Protein Deficiency;457
5.9.3.2.2;3.2.2 Prenatal Vitamin D Deficiency;457
5.9.3.3;3.3 Obstetric Complications;458
5.9.3.3.1;3.3.1 Cesarean Section;458
5.9.3.3.2;3.3.2 Perinatal Hypoxia;459
5.9.3.3.3;3.3.3 Placental Insufficiency;460
5.9.3.4;3.4 Prenatal/Postnatal Stress;460
5.9.3.4.1;3.4.1 Prenatal Stress;460
5.9.3.4.2;3.4.2 Maternal Deprivation;462
5.9.3.5;3.5 Postweaning Social Isolation;462
5.9.3.5.1;3.5.1 Isolation Rearing: Neuroanatomical Abnormalities;463
5.9.3.5.2;3.5.2 Isolation Rearing: Behavioral Abnormalities;464
5.9.3.5.3;3.5.3 Discussion of Isolation-Rearing Model;465
5.9.4;4 Heuristic Neurodevelopmental Models;466
5.9.4.1;4.1 Neonatal Ventral Hippocampal Lesion Model;466
5.9.4.1.1;4.1.1 Neonatal Ventral Hippocampal Lesion Model: Behavioral Studies;466
5.9.4.1.2;4.1.2 Neonatal Ventral Hippocampal Lesion Model: Neuropathological Studies;467
5.9.4.1.3;4.1.3 Conclusions for nVH Lesion Model;468
5.9.4.2;4.2 Prenatal Toxin;469
5.9.4.3;4.3 Postnatal/Neonatal NMDA Antagonists;469
5.9.5;5 Discussion;470
5.9.6;References;472
6;Part III: Neural substrates of schizophrenia;490
6.1;Prefrontal Cortical Circuits in Schizophrenia;491
6.1.1;1 Introduction;492
6.1.1.1;1.1 Working Memory Impairments and Dorsolateral Prefrontal Cortex Circuitry;492
6.1.2;2 Pathology of DLPFC Circuitry in Schizophrenia;494
6.1.2.1;2.1 Abnormalities in Pyramidal Neuron Anatomy and Glutamatergic Signaling;494
6.1.2.2;2.2 Abnormalities in GABA Signaling;497
6.1.2.3;2.3 Alterations in the Dopamine Neurotransmitter System;498
6.1.2.4;2.4 Pathophysiological Consequences of Altered DLPFC Circuitry on Cognitive Functioning in Schizophrenia;499
6.1.3;3 Cortical Circuitry Alterations Beyond the DLPFC;500
6.1.4;4 Cannabis Use and Schizophrenia;501
6.1.4.1;4.1 Clinical Effects of Cannabis Use in Schizophrenia;501
6.1.4.2;4.2 Potential Impact of Cannabis Use of Altered Neurotransmitter Systems in Schizophrenia;503
6.1.4.3;4.3 Endogenous Cannabinoid System and Schizophrenia;504
6.1.5;5 From Pathology to New Therapeutic Approaches;505
6.1.6;References;506
6.2;Thalamic Pathology in Schizophrenia;515
6.2.1;1 Introduction;516
6.2.2;2 The Thalamus Is Uniquely Suited to Modulate Signals Passing to the Cortex;517
6.2.3;3 Syndromes of Thalamic Dysfunction and Their Relevance to Schizophrenia;518
6.2.4;4 Postmortem Evidence: Structural Changes;520
6.2.5;5 Postmortem Evidence: Neurochemical Changes;521
6.2.6;6 Evidence from Neuroimaging;521
6.2.6.1;6.1 Lower Thalamic Volume Is Frequently Seen in Schizophrenia: Changes May Be Localized to the MDN, the Anterior Nuclei, and the Pulvinar;521
6.2.6.2;6.2 Medication Effects;522
6.2.6.3;6.3 Studies at the Onset of Psychosis, and Longitudinal Data;523
6.2.6.4;6.4 Imaging Studies in Relatives of Subjects with Schizophrenia;524
6.2.6.5;6.5 Other Types of Neuroimaging (fMRI, PET, SPECT, DTI);524
6.2.6.6;6.6 The Limitations of Neuroimaging: Why the Conflicting Results?;527
6.2.7;7 Thalamic Pathology in Schizophrenia: Clinical Correlates;528
6.2.8;8 Dysfunction in Thalamocortical Circuits;529
6.2.9;References;530
6.3;Hippocampal Pathology in Schizophrenia;535
6.3.1;1 Introduction;536
6.3.2;2 The Human Hippocampus;536
6.3.3;3 The Hippocampus in Neuropsychiatric Disorders;537
6.3.4;4 Models of Hippocampal Dysfunction in Schizophrenia;538
6.3.5;5 Evidence of Hippocampal Dysfunction in Schizophrenia;540
6.3.5.1;5.1 Hippocampal Volume Change in Schizophrenia;540
6.3.5.2;5.2 Hippocampal Neurons in Schizophrenia;541
6.3.5.2.1;5.2.1 Hippocampal Neuron Number;541
6.3.5.2.2;5.2.2 Glutamatergic Neurotransmission;542
6.3.5.2.3;5.2.3 GABAergic Neurons;543
6.3.5.2.4;5.2.4 Other Neurotransmitters;544
6.3.5.3;5.3 Genetic Mechanisms of Hippocampal Pathology in Schizophrenia;544
6.3.5.4;5.4 Hippocampal Function and Schizophrenia;546
6.3.5.4.1;5.4.1 Hippocampal Activity at Rest in Schizophrenia;546
6.3.5.4.2;5.4.2 Hippocampal Activity and Cognitive Function in Schizophrenia;547
6.3.6;6 Animal Models;548
6.3.7;7 Critical Review of Findings and Directions for Future Studies;549
6.3.8;References;550
6.4;Integrative Circuit Models and Their Implications for the Pathophysiologies and Treatments of the Schizophrenias;560
6.4.1;1 Introduction;561
6.4.2;2 Distributed Neural Dysfunction: The ``Hole´´ Thing Is Wrong;563
6.4.3;3 Now That We Know This, What Do We Ask?;567
6.4.3.1;3.1 Primary Versus Secondary?;567
6.4.3.2;3.2 Clinical Correlates?;568
6.4.3.3;3.3 Different Etiologies?;568
6.4.3.4;3.4 Risk Markers?;569
6.4.3.5;3.5 Which Target?;571
6.4.4;4 Where Does This Lead Us?;573
6.4.4.1;4.1 The Fourth Option;574
6.4.4.2;4.2 Old News, New Urgency;576
6.4.5;5 Conclusion;578
6.4.6;References;579
7;Part IV: Genetic and molecular substratesof schizophrenia;589
7.1;Experimental Approaches for Identifying Schizophrenia Risk Genes;590
7.1.1;1 Introduction;591
7.1.2;2 Linkage Mapping;591
7.1.3;3 Association Mapping;594
7.1.4;4 Identifying Genes Through Structural Chromosomal Variations;600
7.1.5;5 Re-Sequencing;605
7.1.6;References;606
7.2;Epigenetics of Schizophrenia;614
7.2.1;1 Introduction;615
7.2.2;2 Histone Modifications and DNA Methylation;616
7.2.3;3 Findings in Schizophrenia Postmortem Brain;618
7.2.4;4 Reproducibility of Epigenetic Alterations in Schizophrenia Postmortem Brain;620
7.2.5;5 Cellular Specificity of Epigenetic Markings;621
7.2.6;6 Epigenetic Markings in Brain: How Stable?;622
7.2.7;7 Implications for the Neurobiology of Schizophrenia;623
7.2.8;8 Chromatin Remodeling and Antipsychotic Medication;624
7.2.9;9 Synopsis and Outlook;625
7.2.10;References;625
7.3;Molecules, Signaling, and Schizophrenia;632
7.3.1;1 Introduction;633
7.3.2;2 AKT1 Gene and the AKT/GSK3beta Signaling Pathway;634
7.3.2.1;2.1 Neuronal Plasticity;635
7.3.2.2;2.2 Dopamine Signaling;636
7.3.2.3;2.3 GSK3beta Signaling;637
7.3.3;3 PPP3CC Gene and the Calcineurin Signaling Pathway;638
7.3.3.1;3.1 Dopamine Signaling;639
7.3.3.2;3.2 Transcriptional Regulation;640
7.3.3.3;3.3 Synaptic Plasticity and Neurotransmission;640
7.3.3.4;3.4 Nitric Oxide Signaling;641
7.3.3.5;3.5 Vesicle Trafficking;641
7.3.3.6;3.6 Cytoskeletal Phosphorylation;642
7.3.4;4 DISC1 Gene and the cAMP and GSK3/Wnt Signaling Pathways;642
7.3.4.1;4.1 Disc1 and cAMP Signaling;644
7.3.4.1.1;4.1.1 PDE4 and Psychiatric Disorders;646
7.3.4.1.2;4.1.2 Adenylyl Cyclase and Psychiatric Disorders;647
7.3.4.1.3;4.1.3 cAMP-Dependent Downstream Signaling and Schizophrenia;648
7.3.4.1.3.1;Dopamine Signaling;648
7.3.4.1.3.2;EPAC-Mediated Signaling;649
7.3.4.2;4.2 Disc1 and GSK3beta Signaling;649
7.3.5;5 General Summary;649
7.3.6;References;651
8;Index;660