Behavioral Neurobiology of Schizophrenia and Its Treatment (eBook)

Preface 6
Contents 10
Contributors 14
Part I: Function, Outcome and Treatmentin Schizophrenia 20
Assessing Function and Functional Outcome in Schizophrenia 21
1 Introduction 22
1.1 Functional Dimensions 22
1.2 Recent Reviews and Overviews of Measures of Functioning in Schizophrenia 24
2 Construct Validity 25
2.1 Functional Outcome as an Experiential Process 26
2.2 Environmental Moderators of the Functional Dimensions 28
3 Ecological Validity 29
3.1 Verisimilitude and Veridicality 30
3.2 Observation in Naturalistic Environments 32
4 Conclusion 34
References 34
Antipsychotics and Metabolics in the Post-CATIE Era 40
1 Introduction 41
2 Sources of Cardiovascular Risk 43
3 The Cardiovascular and Metabolic Risk Profile of Subjects Entering the CATIE Schizophrenia Trial 46
4 The Impact of Antipsychotic Treatment on Cardiovascular and Metabolic Outcomes in the CATIE Schizophrenia Trial 47
4.1 Metabolic Outcomes 47
4.2 Framingham Cardiovascular Risk 48
4.3 Outcomes with Novel Biomarkers 50
5 The Post-CATIE Era 50
5.1 Clinical Conclusions 50
5.2 Hypotheses on Schizophrenia and Metabolic Risk, and Adiposity-Independent Drug Effects 52
6 Conclusions 54
References 54
Pharmacological Strategies for Enhancing Cognition in Schizophrenia 60
1 Introduction 61
2 Cholinergic Agents 63
2.1 Cholinesterase Inhibitors 64
2.2 Nicotine, Nicotinic Receptor Agonists, and Muscarinic Receptor Agonists 68
3 Glutamatergic Agents 77
3.1 Glycine Allosteric Modulators 77
3.2 AMPA Receptor Modulators 78
3.3 Phosphodiesterase 5 Inhibitors 83
3.4 NMDA Receptor Antagonists 83
4 Gamma-Aminobutyric Acid Modulating Agents 84
5 Dopaminergic Agents 87
5.1 Indirect Dopamine Agonists 88
5.2 Atomoxetine and Amantadine 88
5.3 Selective Dopamine Agonists 93
6 Modafinil 94
7 Other Agents 97
8 Conclusions 100
References 102
Treatment Implications of the Schizophrenia Prodrome 114
1 Introduction 115
1.1 Early Identification of Psychotic Illness 117
1.2 Duration of Untreated Psychosis: Individual and Public Health Concern 117
1.3 Identifying and Predicting Risk for Psychotic Illnesses 118
1.4 Review of Treatment Studies in the Psychotic Prodrome 121
1.5 Nonpharmacologic Interventions 122
1.6 Psychopharmacologic Interventions 123
1.7 Pharmacologic Potential for Neuroprotection 124
1.8 Preliminary Treatment Recommendations 126
1.9 Ethical Implications 126
1.10 Development of Clinical Staging Criteria 128
1.11 Recommended Treatment Guidelines 129
1.12 General Summary 132
References 132
Antipsychotic Drug Development 139
1 Introduction 140
2 Dopamine D2 Receptors: Antagonism, Inverse Agonism, and Partial Agonism 141
3 Dopamine D3 Receptors: Cognition and ``Optimized Antagonism´´ at D3 Versus D2 Receptors 145
4 Serotonin 5-HT2A Receptors: Dopamine Brakes 146
5 Serotonin 5-HT1A Receptors: Dopamine Accelerators 146
6 Serotonin 5-HT2C Receptors 147
7 Serotonin 5-HT7 Receptors 148
8 Glutamatergic Receptors: NMDA and mGluR 148
9 Glycine Agonists 150
10 Receptors That Mediate Side Effects 150
11 Conclusion 151
References 151
Antipsychotic Dosing and Drug Delivery 156
1 Background 157
2 History 158
3 Dopamine Hypothesis 158
4 D2 Mechanism of Antipsychotic Medication 159
5 Clozapine 160
6 Genesis and Interpretation of ``Atypicality´´ 160
7 Current State of Affairs 161
8 Dosing 161
8.1 Chlorpromazine Equivalents 161
8.2 Other Contributions (Non-D2) to Efficacy 164
8.2.1 Potential Benefits of Continuous Infusion 166
8.2.2 Alternative Hypothesis 167
9 Adherence 168
9.1 Background and Clinical Perspective 168
9.1.1 Adherence Rates 168
9.1.2 Relapse Rates as a Function of Adherence 168
9.1.3 Causes of Poor Adherence 169
9.2 Development of Depots 169
9.2.1 Clinical Studies and Meta-Analyses Comparing Depots to Oral Administration 169
9.2.2 Barriers to Creating Depots for More Agents 170
9.3 Development of Polymer-Based Microsphere Systems to Overcome Limitations of Chemistry 170
9.4 Potential Extension to Implants 171
9.4.1 Biodegradable Versus Nonbiodegradable 171
Nondegradable 171
Biodegradable Systems 172
9.4.2 PLGA/PLA 172
9.4.3 Poly(epsi-Caprolactone) 173
9.4.4 Drug Release Mechanisms 174
9.4.5 Erosion 174
9.4.6 Diffusion 175
9.4.7 Advantages 176
Duration 176
Reversibility 177
9.4.8 Limitations 178
Physical Drug Characteristics 178
Stability of the Molecule in a Physiological Environment 178
Ethical Considerations 179
Extension to Other Areas 180
9.5 Transdermal Delivery Systems 180
9.5.1 Potential Benefits 180
9.5.2 Passive Systems 182
9.5.3 Active Iontophoretic Systems 182
9.5.4 Limitations 183
9.6 Barriers to Development of Novel Delivery Systems 183
9.6.1 Long Clinical Trial Length 183
9.6.2 Inclusion of Controls in Studies of 6-Month Exposure to Antipsychotic Medications 184
9.6.3 Placebo Arm in Patients for Length of Time Needed to Truly Test a 6-Month Delivery System 184
10 Summary and Conclusions 185
References 185
Part II: Experimental measures of brain functionand dysfunction in schizophenia 193
Functional Brain Imaging in Schizophrenia: Selected Results and Methods 194
1 Introduction 195
2 Critical Regions 196
2.1 Positive Symptoms 197
2.1.1 Spontaneous Presentation 198
2.1.2 Brain Activation Studies 202
2.1.3 Comments 203
2.2 Negative Symptoms 203
2.2.1 Studies of Uncontrolled Mental State 204
2.2.2 Studies of Brain Activation: Working Memory 206
2.2.3 Summary and Comments 211
3 Brain Systems 212
3.1 Functional Connectivity 212
3.2 Summary and Comments 218
4 Final Comments and Emerging Trends 219
References 220
Neurochemical Imaging in Schizophrenia 228
1 Introduction 229
2 Brief Overview of Neurochemical Imaging Techniques 230
3 Imaging Neurotransmitter Systems 232
3.1 Dopamine 232
3.1.1 Striatal DA Parameters 232
D2 Receptors 232
Baseline Striatal D2 Receptor Density 232
DA Release: Pharmacological Challenge Studies 234
Baseline DA Release 234
Striatal D1 Receptors 235
Dopamine Transporters 235
DA Synthesis 236
3.1.2 Extrastriatal Dopamine 237
D2 Receptors 237
Extrastriatal D1 Receptors 237
3.2 Serotonin 238
3.2.1 5-HT2A Receptors 239
3.2.2 5-HT1A Receptors 239
3.2.3 Serotonin Transporters 240
3.3 Gamma-Aminobutyric Acid 240
3.4 N-Methyl-d-Aspartic Acid and Glutamate 241
4 Occupancy Studies (Pharmacological Studies) 241
4.1 DA Receptor Occupancy 242
4.1.1 D2 Receptor Occupancy 242
Implications for Treatment 242
4.1.2 D1 Receptor Occupancy 244
4.2 Serotonin Occupancy 244
4.2.1 5-HT2A Receptor Occupancy 244
4.2.2 5-HT1A Receptor Occupancy 245
5 Future Directions 245
References 246
A Selective Review of Volumetric and Morphometric Imaging in Schizophrenia 256
1 Introduction 257
2 Limbic/Paralimbic Regions 258
3 Prefrontal Cortical Regions 269
4 Caudate Nucleus 277
5 Neocortical Temporal Lobe 281
6 Conclusion 289
References 290
Neurophysiological Measures of Sensory Registration, Stimulus Discrimination, and Selection in Schizophrenia Patients 295
1 Introduction 296
1.1 Automatic and Attention Dependent Processes 297
1.2 Event-Related Potentials 298
1.3 The Oddball Paradigm 299
1.4 Basic Processes 301
2 N1 ERP 302
2.1 N1 Deficits in Schizophrenia 303
2.2 N1 Stability, Reliability, and Heritability 304
3 MMN ERP 305
3.1 MMN Deficits in Schizophrenia 306
3.2 MMN Stability, Reliability, and Heritability 308
4 P300 ERP 309
4.1 P300 Deficits in Schizophrenia 310
4.2 P3 Stability, Reliability, and Heritability 311
5 Discussion 312
References 313
Eye Tracking Dysfunction in Schizophrenia: Characterization and Pathophysiology 322
1 Introduction 323
2 Components of the Smooth Pursuit Eye Tracking Response 326
3 Characterization of ETD 329
4 Pathophysiology of ETD 333
4.1 Behavioral Evaluations of the Contribution of Motion Processing to ETD 333
4.1.1 Psychophysical Judgment Studies of Motion Perception 334
4.1.2 Saccadic Studies of Motion Perception 341
4.1.3 Pursuit Initiation Studies 341
4.2 Extraretinal Processes in Pursuit 342
4.3 Neuroimaging of Pursuit and Component Processes 345
5 Association Between Genetic Polymorphisms and ETD 347
6 Summary 348
References 348
Prepulse Inhibition of the Startle Reflex: A Window on the Brain in Schizophrenia 359
1 Background of PPI Studies 360
2 Prepulse Inhibition Deficits in Schizophrenia Spectrum (and Other) Patients 363
3 Sex, Symptoms, Cognitive, and Functional Correlates of PPI Deficits in Schizophrenia Patients 365
4 Pharmacological Studies of PPI in Human Subjects Relevant to Schizophrenia 365
4.1 Dopamine 366
4.2 Nicotine 367
5 Antipsychotic Medications in Schizophrenia Patients 368
6 Genomic Influences on PPI in Schizophrenia 369
7 Summary and Future Directions 373
References 375
Neurocognition in Schizophrenia 382
1 Introduction 383
2 General Intellectual Functioning 384
3 Attention 385
4 Processing Speed 386
5 Executive Functioning 386
6 Learning and Memory 388
7 Language 389
8 Visual Perceptual/Constructional Skills 390
9 Fine Motor Skills 390
10 Social Cognition 391
11 Deficits Among Populations at Risk and Endophenotypes 392
12 Longitudinal Studies of Neuropsychological Deficits 393
13 Future Directions of Research 394
References 395
Animal Models of Schizophrenia 400
1 Introduction 401
2 Criteria Used to Validate Animal Models 404
2.1 Reliability 404
2.2 Face Validity 405
2.3 Predictive Validity 405
2.4 Construct Validity 405
2.5 Etiological Validity 406
3 Modeling Schizophrenia in Animals 406
4 Behavioral Measures by Symptom Group 407
4.1 Positive Symptoms 407
4.2 Negative Symptoms 408
4.2.1 Progressive Ratio Breakpoint Studies 408
4.2.2 Intracranial Self-Stimulation 409
4.3 Cognitive Symptoms 409
4.3.1 Attentional Dysfunction 410
5-Choice Serial Reaction-Time Task 410
Sustained Attention Task 410
4.3.2 Executive Function 410
Attentional Set-Shifting Task 410
4.3.3 Working Memory 411
Radial Arm Maze 411
Odor Span Task 411
4.3.4 Visual Learning and Memory 412
Morris Water Maze 412
Novel Object Recognition Task 412
4.4 Sensorimotor Gating Paradigms 412
4.4.1 Prepulse Inhibition 412
4.4.2 Auditory Gating 413
4.5 Latent Inhibition 413
5 Experimental Manipulations for Animal Models of Schizophrenia 414
5.1 Dopaminergic Agonist Models 414
5.1.1 Acute Models 415
5.1.2 Repeat Administration Models 415
5.2 Glutamatergic Antagonist Models 416
5.2.1 Acute Models 417
5.2.2 Repeated Dosing Models 417
5.3 Serotonergic Agonist Models 418
5.4 Cholinergic Antagonist Models 419
5.5 Lesion Models 420
5.6 Genetic Models for Schizophrenia 421
5.6.1 Schizophrenia as a Genetic Disease 421
5.6.2 Candidate Susceptibility Genes for Schizophrenia 421
Human Genetic Linkage and Association 422
Neuregulin-1 422
Dysbindin 422
Cytogenetic Studies 423
Disrupted in Schizophrenia 1 423
COMT 423
NPAS3 424
5.7 Candidate Genes from Animal Models 424
5.7.1 Sp4 424
5.7.2 Copy Number Variation 424
5.7.3 Chromosome 22q11 Deletion 425
5.7.4 Chromosome 15q13.3 Deletion 425
5.8 Transgenic Mouse Models 425
5.8.1 Neuregulin 425
5.8.2 Dysbindin 426
5.8.3 DISC1 426
5.8.4 COMT 427
5.8.5 CHRNA7 428
6 Conclusions 428
References 429
Models of Neurodevelopmental Abnormalities in Schizophrenia 443
1 Neurodevelopmental Models of Schizophrenia 445
1.1 Developmental Theory of Schizophrenia 445
1.2 Animal Models of Developmental Hypothesis 446
2 Behavioral Measures 447
2.1 Spontaneous and Drug-Induced Locomotor Activity 448
2.2 Gating Deficits 448
2.3 Attention 449
2.4 Cognitive Deficits 449
2.5 Social Interaction 450
3 Epidemiologic-Based Developmental Manipulations 450
3.1 Viral and Immune-Activating Models of Schizophrenia 451
3.1.1 Prenatal Viral Exposure 453
3.1.2 Prenatal PolyI:C Exposure 453
3.1.3 Prenatal LPS Exposure 454
3.1.4 Role of Cytokines in Prenatal Immune Models 455
3.1.5 Neonatal Immune Activation 455
3.1.6 Discussion of Immune Models 456
3.2 Maternal Malnutrition 456
3.2.1 Prenatal Protein Deficiency 457
3.2.2 Prenatal Vitamin D Deficiency 457
3.3 Obstetric Complications 458
3.3.1 Cesarean Section 458
3.3.2 Perinatal Hypoxia 459
3.3.3 Placental Insufficiency 460
3.4 Prenatal/Postnatal Stress 460
3.4.1 Prenatal Stress 460
3.4.2 Maternal Deprivation 462
3.5 Postweaning Social Isolation 462
3.5.1 Isolation Rearing: Neuroanatomical Abnormalities 463
3.5.2 Isolation Rearing: Behavioral Abnormalities 464
3.5.3 Discussion of Isolation-Rearing Model 465
4 Heuristic Neurodevelopmental Models 466
4.1 Neonatal Ventral Hippocampal Lesion Model 466
4.1.1 Neonatal Ventral Hippocampal Lesion Model: Behavioral Studies 466
4.1.2 Neonatal Ventral Hippocampal Lesion Model: Neuropathological Studies 467
4.1.3 Conclusions for nVH Lesion Model 468
4.2 Prenatal Toxin 469
4.3 Postnatal/Neonatal NMDA Antagonists 469
5 Discussion 470
References 472
Part III: Neural substrates of schizophrenia 490
Prefrontal Cortical Circuits in Schizophrenia 491
1 Introduction 492
1.1 Working Memory Impairments and Dorsolateral Prefrontal Cortex Circuitry 492
2 Pathology of DLPFC Circuitry in Schizophrenia 494
2.1 Abnormalities in Pyramidal Neuron Anatomy and Glutamatergic Signaling 494
2.2 Abnormalities in GABA Signaling 497
2.3 Alterations in the Dopamine Neurotransmitter System 498
2.4 Pathophysiological Consequences of Altered DLPFC Circuitry on Cognitive Functioning in Schizophrenia 499
3 Cortical Circuitry Alterations Beyond the DLPFC 500
4 Cannabis Use and Schizophrenia 501
4.1 Clinical Effects of Cannabis Use in Schizophrenia 501
4.2 Potential Impact of Cannabis Use of Altered Neurotransmitter Systems in Schizophrenia 503
4.3 Endogenous Cannabinoid System and Schizophrenia 504
5 From Pathology to New Therapeutic Approaches 505
References 506
Thalamic Pathology in Schizophrenia 515
1 Introduction 516
2 The Thalamus Is Uniquely Suited to Modulate Signals Passing to the Cortex 517
3 Syndromes of Thalamic Dysfunction and Their Relevance to Schizophrenia 518
4 Postmortem Evidence: Structural Changes 520
5 Postmortem Evidence: Neurochemical Changes 521
6 Evidence from Neuroimaging 521
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 Medication Effects 522
6.3 Studies at the Onset of Psychosis, and Longitudinal Data 523
6.4 Imaging Studies in Relatives of Subjects with Schizophrenia 524
6.5 Other Types of Neuroimaging (fMRI, PET, SPECT, DTI) 524
6.6 The Limitations of Neuroimaging: Why the Conflicting Results? 527
7 Thalamic Pathology in Schizophrenia: Clinical Correlates 528
8 Dysfunction in Thalamocortical Circuits 529
References 530
Hippocampal Pathology in Schizophrenia 535
1 Introduction 536
2 The Human Hippocampus 536
3 The Hippocampus in Neuropsychiatric Disorders 537
4 Models of Hippocampal Dysfunction in Schizophrenia 538
5 Evidence of Hippocampal Dysfunction in Schizophrenia 540
5.1 Hippocampal Volume Change in Schizophrenia 540
5.2 Hippocampal Neurons in Schizophrenia 541
5.2.1 Hippocampal Neuron Number 541
5.2.2 Glutamatergic Neurotransmission 542
5.2.3 GABAergic Neurons 543
5.2.4 Other Neurotransmitters 544
5.3 Genetic Mechanisms of Hippocampal Pathology in Schizophrenia 544
5.4 Hippocampal Function and Schizophrenia 546
5.4.1 Hippocampal Activity at Rest in Schizophrenia 546
5.4.2 Hippocampal Activity and Cognitive Function in Schizophrenia 547
6 Animal Models 548
7 Critical Review of Findings and Directions for Future Studies 549
References 550
Integrative Circuit Models and Their Implications for the Pathophysiologies and Treatments of the Schizophrenias 560
1 Introduction 561
2 Distributed Neural Dysfunction: The ``Hole´´ Thing Is Wrong 563
3 Now That We Know This, What Do We Ask? 567
3.1 Primary Versus Secondary? 567
3.2 Clinical Correlates? 568
3.3 Different Etiologies? 568
3.4 Risk Markers? 569
3.5 Which Target? 571
4 Where Does This Lead Us? 573
4.1 The Fourth Option 574
4.2 Old News, New Urgency 576
5 Conclusion 578
References 579
Part IV: Genetic and molecular substratesof schizophrenia 589
Experimental Approaches for Identifying Schizophrenia Risk Genes 590
1 Introduction 591
2 Linkage Mapping 591
3 Association Mapping 594
4 Identifying Genes Through Structural Chromosomal Variations 600
5 Re-Sequencing 605
References 606
Epigenetics of Schizophrenia 614
1 Introduction 615
2 Histone Modifications and DNA Methylation 616
3 Findings in Schizophrenia Postmortem Brain 618
4 Reproducibility of Epigenetic Alterations in Schizophrenia Postmortem Brain 620
5 Cellular Specificity of Epigenetic Markings 621
6 Epigenetic Markings in Brain: How Stable? 622
7 Implications for the Neurobiology of Schizophrenia 623
8 Chromatin Remodeling and Antipsychotic Medication 624
9 Synopsis and Outlook 625
References 625
Molecules, Signaling, and Schizophrenia 632
1 Introduction 633
2 AKT1 Gene and the AKT/GSK3beta Signaling Pathway 634
2.1 Neuronal Plasticity 635
2.2 Dopamine Signaling 636
2.3 GSK3beta Signaling 637
3 PPP3CC Gene and the Calcineurin Signaling Pathway 638
3.1 Dopamine Signaling 639
3.2 Transcriptional Regulation 640
3.3 Synaptic Plasticity and Neurotransmission 640
3.4 Nitric Oxide Signaling 641
3.5 Vesicle Trafficking 641
3.6 Cytoskeletal Phosphorylation 642
4 DISC1 Gene and the cAMP and GSK3/Wnt Signaling Pathways 642
4.1 Disc1 and cAMP Signaling 644
4.1.1 PDE4 and Psychiatric Disorders 646
4.1.2 Adenylyl Cyclase and Psychiatric Disorders 647
4.1.3 cAMP-Dependent Downstream Signaling and Schizophrenia 648
Dopamine Signaling 648
EPAC-Mediated Signaling 649
4.2 Disc1 and GSK3beta Signaling 649
5 General Summary 649
References 651
Index 660