Animal and Translational Models for CNS Drug Discovery: Psychiatric Disorders (eBook)

Front Cover 1
Animal and Translational Models for CNS Drug Discovery 4
Copyright Page 5
Contents 8
Preface 18
Acknowledgements 40
List of Contributors 42
CHAPTER 1 The Discovery and Development of Pharmacotherapy for Psychiatric Disorders: A Critical Survey of Animal and Translational Models and Perspectives for Their Improvement 46
Introduction: Psychiatric Disorders, Common Features, and Common Challenges 47
Animal Models for, not of, Psychiatric Disorders: Basic Goals 47
Understanding Pathogenesis: Finding New Targets for Improved Management 47
Characterizing Mechanisms of Action of Clinically Effective Drugs 49
Predicting Clinical Efficacy and Safety: The Core Concern of Drug Discovery 50
Complementary Experimental Procedures for Validation of Models, Targets, and Drugs 51
The Impact of "Rational" Drug Discovery on the Use of Animal Models 54
Translational Models: Linking Preclinical and Clinical Studies 56
Revising a Paradigm: New Procedures and New Possibilities 56
Relating Drug Exposure to Drug Doses and Actions 58
Circulating Biomarkers: From Hormones to Genes 58
Sensorimotor Gating, Cognitive Performance, and Motor Behavior 60
Quantitative Electroencephalography 61
Functional Magnetic Resonance Imaging (fMRI) 62
Proton Magnetic Resonance Spectroscopy 64
Positron Emission Tomography and Single Photon Emission Computerized Tomography 65
Animal and Translational Models for Psychiatric Disorders: Scope for Refinement 68
Modeling New Targets: Glia, Intracellular Proteins, Neuronal Plasticity, and Epigenesis 68
Prevention of Psychiatric Disorders and Alleviating Stress 71
Modeling Non-pharmacotherapeutic Strategies 72
Modeling Long-term and Unwanted Drug Actions 73
Modeling Drug Combinations 75
Modeling Drug Actions in Specific Populations 75
New Concepts for Understanding Psychiatric Disorders and Facilitating Drug Discovery 76
Concluding Comments 78
Acknowledgements 79
References 80
CHAPTER 2 Drug Discovery and Development Initiatives at the National Institute of Mental Health: From Cell-Based Systems to Proof of Concept 104
The Need for New Treatments for Mental Disorders 105
Models in Drug Discovery of Neuropsychiatric Disorders 106
NIMH Support for Discovery Science and Basic Neuroscience Research 107
Role of NIMH in Drug Discovery and Model Development 107
Grant Support for Drug Discovery and Mechanism of Action Studies 108
NIMH Resource Support for Drug Discovery 108
NIH Resource Support for Drug Discovery 109
NIMH Initiatives Supporting Drug Discovery and Target Identification 109
NIMH Initiatives for Drug Development: Preclinical, First in Human, and Clinical Studies 111
Facilitating the Development and Evaluation of Preclinical Models for Therapeutic Discovery 113
Workshops Addressing Barriers in Treatment Development 113
Identification of Key Measures of Clinical Efficacy: The Example of Cognitive Deficits in Schizophrenia 113
Measurement and Treatment Research to Improve Cognition in Schizophrenia 114
NIMH Workshops on Developing Assessment Tools for Cognitive Functioning 114
Treatment Units for Research on Neurocognition and Schizophrenia 115
Future Opportunities for Model Discovery 115
Development of Biomarkers for Mental Disorders 115
Modeling Genetic, Developmental, and Environmental Risk Factors 116
Modeling Key Deficits in Mental Disorders 117
Application of Data-mining Technology in Model Evaluation and Drug Discovery 117
Conclusions 118
References 118
CHAPTER 3 Issues in the Design and Conductance of Clinical Trials 120
Introduction 120
New Drug Development 121
Phase 0 122
Phase I 123
Phase II 124
Phase III 126
Phase IV 127
Pragmatic Evaluation of Approved Drugs 128
Clinical Trial Design and Implementation 128
Patient Populations 129
Duration of Trials 130
Sample Size and Statistical Power 131
Pharmacological Treatments 132
Outcomes 133
Improvements are Needed and Translational Models will Help 134
Patient Population 134
Pharmacological Treatments 135
Duration of Trials 135
Outcome Measures 136
The Business of Research 137
Conclusions 138
References 139
CHAPTER 4 Challenges for Translational Psychopharmacology Research: The Need for Conceptual Principles 142
Introduction 142
What Exactly is Modeled in Preclinical Procedures? are Experimental Procedures Screens, Assays, Models, or Paradigms? 143
The Theoretical Assumptions for Selecting Environmental, Neurochemical and Genetic Manipulations in Order to Model Core Symptoms 148
Which Kind of Validity is Necessary for a Preclinical Model to Render it Translatable to Clinical Concerns? 152
How to Study Affective Processes in Preclinical Models and Translate them to the Clinic? 153
Conclusions 155
References 155
CHAPTER 5 Developing Novel Anxiolytics: Improving Preclinical Detection and Clinical Assessment 162
Introduction 162
Measuring "Anxiety" in Animals 164
Rodent Models of "Pathological" Anxiety 165
Preclinical Tests for Anxiolytic Drug Discovery 167
Translational Models for Anxiolytic Drug Discovery 169
Challenges in Measuring Human Anxiety and Response to Treatments 169
Lost in Translation? 172
Future Perspectives 172
References 174
CHAPTER 6 Animal Models of Obsessive–Compulsive Disorder: From Bench to Bedside via Endophenotypes and Biomarkers 178
Introduction 179
Clinical Aspects 179
Obsessions and Compulsions 179
Phenomenology and Psychobiology of Subtypes and Spectrums 180
Pharmacotherapy of OCD 182
Where to Next in Clinical Research? 187
Animal Models of OCD 188
Face, Predictive and Construct Validity of Animal Models 188
Animal Models of OCD 189
Endophenotypes and Biomarkers 195
Stereotypy as a Possible Endophenotype 195
Emotional Biomarkers 195
Neurocognitive Biomarkers 196
Application of Neurocognitive Biomarkers in OCD 198
Conclusion 198
What, Then, are the Next Steps Going Forwards? 199
References 199
CHAPTER 7 Developing More Efficacious Antidepressant Medications: Improving and Aligning Preclinical and Clinical Assessment Tools 210
Introduction 211
The Challenges of Developing the Next Generation of Antidepressants 211
Limitations of Clinical Assessment 213
The Need for Better Antidepressant Therapies 214
Challenges in the Discovery of New Antidepressants 214
Biomarkers and Depression 215
Stress and Depression 215
HPA Axis Markers 216
Synergism of CRH and AVP 217
Glucocorticoids 217
Vasopressin in Major Depression 217
Dynamic Tests of HPA Function and the VP-ergic System 218
HPA Axis as Antidepressant Target 218
Lessons from Clinical Studies of HPA-Axis Modulating Drug Candidates 219
Preclinical Models of Depression in Drug Discovery 220
Future Challenges for Preclinical Models in Drug Discovery 221
Traditional Animal Models of Depression 222
Animal Model of Depression or Test of Antidepressant Activity 224
Endophenotype-style Approaches 225
Genetic Approaches: Toward New Targets 229
Perspectives 230
References 231
CHAPTER 8 Developing New Drugs for Schizophrenia: From Animals to the Clinic 244
Introduction 245
History of Drug Discovery and Current Treatments 247
Unmet Clinical Need 250
Current Understanding of the Neurobiology of Schizophrenia and Disease Hypotheses 251
Neurotransmitter Hypotheses of Schizophrenia 251
Neurodevelopmental Hypotheses of Schizophrenia 253
Structural and Molecular Changes in Schizophrenia 254
Genetic Findings in Schizophrenia 255
Future of Genetic Studies 258
Epigenetics 258
Current Drug Discovery in Schizophrenia 259
Preclinical Models of Aspects of Schizophrenia 259
Experimental/Translational Medicine Approaches 275
Academic-Industry-Government Initiatives in Schizophrenia 276
Future of Drug Discovery in Schizophrenia and Discussion 277
Strategies for Drug Discovery 277
Development of Clinical Studies in Drug Discovery 278
The Importance of Positive Symptoms in Designing Translational Models 280
The Importance of Functional Outcome and Performance-based Assessment 280
Considering the Plasticity of Cognitive Deficits in Schizophrenia 282
Translational Models of Treatment in the Prodrome 282
Pharmacogenetics/Pharmacophenomics 283
Conclusion 283
Acknowledgements 283
References 284
CHAPTER 9 Developing Therapeutics for Bipolar Disorder (BPD): From Animal Models to the Clinic 308
Introduction 309
The Clinical Diagnosis and Management of Bipolar Disorder 309
Currently Indicated Medications for Bipolar Disorder 312
Unmet Needs in Bipolar Disorder 313
Approaches to Drug Discovery for the Treatment of Bipolar Disorder 314
Current Animal Models 315
Mania 317
Depression 320
Mood Instability 322
Evaluation of Dose–Response, Safety, and Tolerability 323
Prospects for New Models 325
A Battery of Symptom-Based Models 325
Insights from the Mechanism of Action of Existing Drugs 326
Endophenotype-Based Models 327
Clinical Testing and Translational Initiatives for Bipolar Disorder 329
Exploring Dose–Effect Relationships 330
Disease Models in Humans 331
Approaches to Evaluating Efficacy in Patients with Bipolar Disorder 331
Conclusions 334
References 335
CHAPTER 10 Towards a Biological Understanding of ADHD and the Discovery of Novel Therapeutic Approaches 346
Introduction 347
Clinical and Neuroscientific Update of ADHD: an Academic Perspective 348
Current Clinical Concepts of ADHD 348
Current Neuroscientific Concepts of ADHD 351
Neurobiology of ADHD 352
Search for Endophenotypes 355
Current Treatment Strategies 356
Targets for Treatment 356
Pharmacological Strategies 357
Non-pharmacological Strategies 358
Need for Novel Treatment Approaches 359
Discovery of Pharmaceutical Treatments for ADHD – from Serendipity to Rational Drug Design 359
The Search for Novel Therapeutic Targets 361
Needed Improvements in Current Pharmaceutical Agents 362
Models Available in Preclinical Drug Discovery 362
Animal Models of ADHD 363
Genetic Models 364
Neurotoxicity Models 365
Behavioral Assays 366
The Need to Develop Preclinical Cognition Assays in Animal Species 369
Translational Biomarkers in ADHD Drug Development 370
Use of Biomarkers in the Drug Development of ADHD Compounds 370
Types of Biomarkers Used in Early Drug Development 372
Challenges in Clinical Development 376
Early Clinical Development for ADHD 377
Timing of Pediatric Studies: Ethical and Regulatory Issues 378
Differential Efficacy in Children Versus Adults 379
Summary 379
Acknowledgments 380
References 380
CHAPTER 11 Preclinical Animal Models of Autistic Spectrum Disorders (ASD) 398
Introduction 399
Clinical Phenomenology of ASD 400
Historical Origins 401
Diagnostic Criteria and Core Symptom Domains of ASD 401
Clinical Measurements of ASD 403
Current Pharmacological Treatment Strategies 405
Translational Research in ASD: Endophenotypes and Genetic Risk Factors 409
ASD Endophenotypes 410
Genetic Risk Factors for ASD 410
Preclinical Modeling of ASD in Animals: Behavioral Assays and ASD Models 411
Behavioral Assays Used to Measure ASD-like Symptoms in Animals 412
Animal Models of ASD 416
Models Based on Candidate ASD Genes 419
Animal Models of Monogenic Disorders with ASD Phenotypes 420
Animal Models of ASD in Drug Discovery Research 421
Translational Roles for Animal Models in ASD Drug Research 421
Model Development and Validation: Issues, Needs, and Challenges 425
Summary and Future Directions 428
References 429
CHAPTER 12 Translational Models of Sleep and Sleep Disorders 440
Introduction 441
Clinical Description of Prevalent Sleep Disorders 442
Insomnia 442
Sleep Apnea 443
Narcolepsy 444
Excessive Daytime Sleepiness 444
Sleep Neurobiology 445
Sleep and its Measurement 445
Localization of Sleep/Wake Brain Regions 446
The Hypocretin/Orexin System 449
Other Neurochemicals Involved in Sleep/Wake Control 451
Sleep Homeostasis and the Timing of Sleep and Wakefulness 453
Animal Models of Sleep 453
Cats 454
Rats 454
Monkeys 456
Aged Animals 458
Sleep Deprivation 460
Insomnia 461
Pharmacological Models of Insomnia 461
Noise Disruption Model of Insomnia 462
Behavioral Stress Model of Insomnia 463
Sleep Apnea 464
Airway Obstruction 464
Intermittent Hypoxia 464
Sleep Fragmentation 465
Sleep and Metabolic Disorders 466
Effects of Metabolism on Sleep/Wake Cycle 466
Animal Models Linking Sleep to Obesity 467
Vaccines 467
Genetic Aspects of Human and Animal Sleep 468
Changes in Sleep State Alter Changes in Gene Expression 469
Evidence for Genetic Control of Sleep/Wake Traits 469
Fruit Flies 470
Inbred Mice 470
Human Studies 472
Candidate Genes for Sleep/Wake Traits 473
Drug Discovery and Pharmacologic Targets for the Treatment of Sleep Disorders 475
How to Change Sleep Pharmaceutical Discovery 478
Conclusions 479
Where are the Novel Medicines? 480
Acknowledgments 481
References 481
Epilogue: Translational Models for the 21st Century: Reminescence, Reflections, and Some Recommendations 502
Introduction 502
References 512
Index 520
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