Behavioral Neurobiology of Anxiety and Its Treatment (eBook)

Preface 6
Contents 10
Contributors 14
Part I: Anxiety Disorders - Clinical 18
Anxiety Disorders Diagnosis: Some History and Controversies 19
1 Introduction 20
2 A Brief History of Anxiety Disorders Classification 20
3 Controversy in Classification of Individual Anxiety Disorders 23
3.1 Agoraphobia Past and Present, in the United States and Elsewhere 23
3.2 Posttraumatic Phenomena 27
3.3 Generalized Anxiety Disorder 28
3.4 OCD and Putatively Related Conditions 30
4 Summary 30
References 31
Epidemiology of Anxiety Disorders 36
1 Introduction 37
2 Lifetime Prevalence and Course 38
2.1 Prevalence 38
2.2 Age-of-onset 39
2.3 Persistence 40
3 Special Issues Concerning Particular Anxiety Disorders 41
3.1 Agoraphobia Without a History of Panic Disorder 41
3.2 Generalized Anxiety Disorder 42
3.3 Obsessive-Compulsive Disorder 42
3.4 Separation Anxiety Disorder 43
4 Comorbidity Among the Anxiety Disorders 43
5 The Societal Costs of Anxiety Disorders 45
6 Conclusion 45
References 47
Comorbidity in Anxiety Disorders 51
1 Introduction 52
2 Psychiatric Disorders Comorbidity in Population-Based Studies of Adults 53
2.1 Concomitant Comorbidity with Mood Disorders 54
2.2 Lifetime Comorbidity with Mood Disorders 54
2.3 Concomitant Comorbidity with Substance Use Disorders 55
2.4 Lifetime Comorbidity with Substance Use Disorders 58
2.5 Comorbidity with Other Psychiatric Disorders 58
2.6 Findings from Prospective Studies 60
3 Psychiatric Disorders Comorbidity in Population-Based Studies of Children and Adolescents 60
3.1 Lifetime Comorbidity of Childhood and Adult Anxiety Disorders 60
3.2 Comorbidity with Mood Disorders 61
3.3 Comorbidity with Substance Use Disorders 61
3.4 Comorbidity with Other Psychiatric Disorders 62
4 Genetic Epidemiologic Approaches to Comorbidity 62
5 Comorbidity with Physical Disorders 63
5.1 Respiratory Conditions 64
5.2 Gastrointestinal Conditions 64
5.3 Allergies and Atopic Disorders 65
5.4 Head Injury 65
5.5 Cardiovascular Conditions 65
5.7 Conclusion 66
6 Future Directions and Conclusions 67
References 67
Part II: Anxiety Disorders - Clinical Neuroscience 74
Genetics 75
1 Clinical Genetics 76
2 Molecular Genetics 77
2.1 Linkage Studies 77
2.2 Cytogenetic Studies 78
2.3 Association Studies/Interaction Analyses/Meta-Analyses 78
2.4 Gene-Environment Interaction Analyses 80
3 Analysis of Intermediate Phenotypes 80
4 Pharmacogenetics 82
5 Discussion and Perspectives 83
References 84
Neuroanatomy of Anxiety 88
1 Introduction 90
2 Pavlovian Fear Conditioning Studies 90
3 Antipredatory Defensive Systems 93
3.1 Amygdalar Systems Involved in Predator Detection 93
3.2 The Hipoccampal Formation and the Contextual Analysis for Predatory Environment 94
3.3 The Medial Hypothalamic Defensive System 94
3.4 The Periaqueductal Gray and the Integration of Antipredatory Responses 95
4 The Septum-Hippocampus and the Behavioral Inhibition System 95
5 The Prefrontal Cortex 97
5.1 mPFC and Conditioned Fear 99
5.2 mPFC and Innate Fear 100
5.3 mPFC and Visceral Reactions to Threat 100
5.4 PFC Responses to Stress 101
6 Clinical Findings and Anxiety Disorders 101
7 Conclusions 103
References 104
Stress and the Neuroendocrinology of Anxiety Disorders 108
1 Stress and Emotional Behavior 109
1.1 Mediators of the Stress Response 110
2 Anxiety Disorders and Stress 112
3 Animal Models of Stress and Anxiety 114
4 The Neurocircuitry of Stress - Implications for Anxiety 117
4.1 Structural and Functional Organization of the Amygdala 118
4.2 Structural and Functional Organization of the BNST 119
4.3 Structural Remodeling of the Amygdala and BNST - Implications for Anxiety and the Stress Response 120
5 Final Remarks 121
References 121
Part III: Animal Models 130
Animal Models of Anxiety and Anxiolytic Drug Action 131
1 Animal Models of Anxiety and Anxiolytic Drug Action: Introduction 132
1.1 Conflict Tests 136
1.2 Fear Potentiated Startle 138
1.3 Defensive Burying 140
1.4 Light-Dark Exploration 143
1.5 Social Interaction 144
1.6 Elevated Plus-Maze 145
1.7 Separation-induced Ultrasonic ``Distress´´ Vocalization 147
2 Summary and Conclusions 151
References 154
Genetic Approaches to Modeling Anxiety in Animals 171
1 Introduction 172
2 Basic Concepts in Animal Modeling of Anxiety Disorders 173
3 Measurable Outcomes in Anxiety Disorders and Animal Models 174
3.1 Measuring Anxiety in Man and Diagnostic Criteria in Anxiety Disorders 175
3.2 Measuring Anxiety in Laboratory Animals 176
4 Genetics of Clinical Anxiety Disorders: Setting the Scene for Animal Models 178
4.1 Gene-Environment Interactions 181
4.2 Endophenotypes: Modeling Behavior and Genetics Together? 182
5 Genetic Approaches in Animal Modeling of Anxiety and Anxiety Disorders 183
5.1 Genotype-to-Phenotype: Targeted Manipulation of Candidate Genes 184
5.1.1 Constitutive Genetic Manipulations 184
5.1.2 Transgenic Rats 187
5.1.3 siRNA and Viral Transfection 188
5.2 Phenotype-to-Genotype 190
5.2.1 Inbred Mouse Strains, Gene-Environment Interactions and Quantitative Trait Loci 190
5.3 Gene Expression Arrays 193
5.4 Random Mutagenesis: Radiation and ENU Screens 195
5.5 Selective Breeding of Rats and Mice 196
6 Conclusion 197
References 198
Part IV: Translational Science 212
Behavioral Correlates of Anxiety 213
1 Introduction: Why Do We Need Behavioral Correlates of Anxiety? 214
2 Startle Reactivity Paradigms 215
2.1 Startle Reactivity to Aversive Images 215
2.2 Startle Reactivity in Darkness 216
2.3 Fear Potentiated Startle to Conditioned Cues 217
2.4 Conditioned Inhibition and Extinction 218
3 Startle Reactivity as a Tool for Predicting Anxious Responses 219
3.1 Do Startle Reflex Measures Predict Clinical Anxiety? 219
4 Can Startle Reactivity Be Used as an Endophenotype for Anxiety? 221
5 Can the Signal Predict Treatment Efficacy? 222
5.1 Benzodiazepines 223
5.2 Serotonin Reuptake Inhibitors 224
5.3 Putative Anxiolytics and Behavioral Treatments 224
6 Emotional Bias Tasks 225
7 Do Attentional Bias Task Measures Predict Clinical Anxiety? 226
8 Do Attentional Bias Tasks Predict Treatment Efficacy? 226
9 Behavioral Avoidance 227
10 Promising Behavioral Tasks in Development 228
11 Final Summary 228
References 229
Challenging Anxiety: A Focus on the Specificity of Respiratory Symptoms 237
1 Introduction 238
2 Panic-Respiration or Anxiety-Respiration Link? 239
3 Respiratory Variables in PD 241
3.1 Respiratory Rate 241
3.2 Partial Pressure of CO2 242
3.3 Tidal Volume and Minute Volume 243
3.4 Respiratory Variability, Sighing, and Approximate Entropy 244
4 Respiration and Phobias 245
4.1 Social Phobia 246
4.2 Blood Injury Phobia 246
4.3 Other Phobias 247
5 Obsessive-Compulsive Disorder 247
6 Generalized Anxiety Disorder 248
7 Posttraumatic Stress Disorder 249
8 Discussion 250
References 254
Functional Neuroanatomy of Anxiety: A Neural Circuit Perspective 259
1 Introduction 260
1.1 Neural Circuitry of Anxiety-Relevant Negative Emotion: Reactivity and Regulation 261
1.2 Core Limbic System 261
1.3 Medial PFC 264
1.4 Explicit and Implicit Emotion Regulation 267
1.5 Hippocampus 269
1.6 Summary 269
1.7 Negative Emotional Processing in Anxiety Disorders: A Meta-Analytic Framework 270
1.8 Generalization of Anxiety Beyond Disorder-Related Material: PTSD and Specific Phobia 273
2 Generalized Anxiety Disorder 274
3 Panic Disorder 275
4 Obsessive-Compulsive Disorder 276
5 Treatment Studies 277
6 Conclusion 278
References 280
Pharmacological Enhancement of Behavioral Therapy: Focus on Posttraumatic Stress Disorder 286
1 Introduction 287
2 Traditional Hypnotherapy and Psychodynamic Treatments 288
3 Cognitive-Behavioral Therapy 289
3.1 Exposure Therapy 289
3.2 Virtual Reality Exposure Therapy 291
3.3 Anxiety Management Techniques 292
3.4 Systematic Desensitization 293
3.5 Eye Movement Desensitization and Reprocessing 293
4 Traditional Combinations of Psychotherapy with Medication 294
4.1 Panic Disorder 295
4.2 Obsessive-Compulsive Disorder 295
4.3 Social Phobia 296
4.4 Posttraumatic Stress Disorder 296
5 Novel Approach: Pharmacotherapy Augmentation of Psychotherapeutic Learning 298
6 Conclusion 301
References 302
Part V: Preclinical and Clinical Psychopharmacology 307
Pharmacological Systems 307
The Pharmacology of Anxiety 308
1 Introduction 309
1.1 The GABAergic System and Anxiety 310
1.2 Early Evidence for the Role of the GABAergic System in Anxiety 311
1.3 The GABAA Receptor and Anxiety 312
1.4 How the BDZ-GABAA Receptor Site Has Contributed to the Understanding of Anxiety 314
1.5 Evidence of a GABA Receptor Abnormality in Brain Imaging Studies 316
1.6 A Glimpse at the Future: How Individual Subunits of the GABAA Receptor Could Contribute to Anxiety 317
1.7 Impaired GABAergic Metabolism in Anxiety Disorders: Additional Approaches to Targeting the GABA System 318
2 Serotonin 319
3 Noradrenaline 323
4 Dopamine 326
5 Glutamate 326
6 Conclusions 328
References 329
GABAA Receptor a2/a3 Subtype-Selective Modulators as Potential Nonsedating Anxiolytics 336
1 Introduction 337
2 Benzodiazepines and the GABAA Receptor 340
3 Identification of MRK-409 and TPA023 342
4 Identification of TPA023B 342
5 Note on Nomenclature 344
6 Comparison of the In Vitro Properties of MRK-409, TPA023, and TPA023B 345
7 Preclinical Pharmacokinetics of MRK-409, TPA023, and TPA023B 345
8 Receptor Occupancy in Rats 349
9 Preclinical Nonsedating Anxiolytic Profiles of MRK-409, TPA023, and TPA023B 350
10 Additional Preclinical Pharmacology 350
10.1 Drug Discrimination 352
10.2 Self Administration 352
10.3 Physical Dependence 353
11 Clinical Pharmacokinetics of MRK-409, TPA023, and TPA023B 353
12 Tolerability of MRK-409, TPA023, and TPA023B in Man 354
13 [11C]Flumazenil PET After Oral Dosing of MRK-409, TPA023, and TPA023B in Man 355
14 Comparison of the Pharmacodynamic Responses of MRK-409 and TPA023 in Man 356
15 Anxiolytic-Like Efficacy of TPA023 357
16 Additional Clinical Data with TPA023 358
17 Summary 359
References 360
Antidepressant Treatment in Anxiety Disorders 366
1 Introduction 367
2 Clinical Evidence on Anxiolytic Activity of Antidepressant Drugs 368
2.1 Generalized Anxiety Disorder 368
2.2 Panic Disorder 369
2.3 Social Anxiety Disorder 370
2.4 Post-Traumatic Stress Disorder 371
2.5 Obsessive-Compulsive Disorder 372
3 Preclinical Evidence 373
3.1 Is Anxiolytic Activity Predicted by Efficacy in Classical Antidepressant Tests? 373
3.2 Efficacy of Antidepressant Drugs in Classical ``Anxiolytic´´ Tests 374
3.2.1 Ethological Models: Exploratory Activity 374
3.2.2 Ethological Models: Social Behavior 374
3.2.3 Unconditioned Stress-Induced Responses 375
3.2.4 Conditioned Fear Tests 375
3.2.5 Conflict Tests 376
3.3 Animal Models of Panic Attacks 376
3.4 Animal Models of Social Anxiety 376
3.5 Animal Models of Post-Traumatic Stress Disorder 377
3.6 Animal Models of Obsessive-Compulsive Disorder 378
3.7 ``Benzodiazepine´´ Versus ``Anxiolytic Activity´´ Tests 378
3.8 Need for New ``Anxiolytic´´ Tests Sensitive to Antidepressant Drug Treatment 379
3.8.1 Social Stress 380
3.8.2 Non-Social Stress 382
3.8.3 Beyond Chronic Stress Procedures 382
4 Mechanisms of Anxiolytic Action of Antidepressant Drugs 384
4.1 Changes in the Neurotransmitter Systems 384
4.2 Neuroanatomical Aspects of Antidepressant Drugs´ Anxiolytic Action 385
4.2.1 Hippocampus 386
4.2.2 Prefrontal Cortex 387
4.3 Cognitive Model of Anxiety Disorders: Implications for Novel Drug Development 388
5 Summary 389
References 390
Metabotropic Glutamate Receptors: Their Therapeutic Potential in Anxiety 396
1 Classes of Glutamate Receptors 397
2 Group I mGlu Receptor Expression in the Brain 398
3 mGlu1 Receptors 398
3.1 Selective Tool Compounds 398
3.2 Preclinical Efficacy 399
4 mGlu5 400
4.1 Selective Tool Compounds 400
5 Efficacy in Anxiety 401
5.1 Preclinically 401
5.2 Clinically 401
6 Group II mGlu Receptor Expression in the Brain 402
6.1 Selective Tool Compounds 403
7 Efficacy in Anxiety 403
7.1 Preclinically 403
7.2 Clinically 404
8 Group III mGlu Receptors 405
9 Receptor Expression 405
10 Group III Selective Ligands 406
10.1 The mGlu4 Receptor 407
10.1.1 Specific Tool Compounds 407
10.1.2 Preclinical Efficacy 407
10.2 The mGlu6 Receptor 407
10.2.1 Specific Tool Compounds 407
10.2.2 Preclinical Efficacy 407
10.3 The mGlu7 Receptor 408
10.3.1 Specific Tool Compounds 408
10.3.2 Preclinical Efficacy 408
10.4 The mGlu8 Receptor 409
10.4.1 Specific Tool Compounds 409
10.4.2 Preclinical Efficacy 409
11 Conclusions 410
Literature 411
Developing Small Molecule Nonpeptidergic Drugs for the Treatment of Anxiety Disorders: Is the Challenge Still Ahead? 419
1 Introduction 420
2 Is there Clinical Proof-of-Concept with Compounds Acting at Neuropeptide Systems? 422
2.1 CRF1 Antagonists 422
2.2 NK1 Antagonists 424
2.3 NK3 Antagonists 425
2.4 CCK2 Antagonists 425
3 Atrial Natriuretic Peptide and Oxytocin 426
4 Is Efficacy Enough? 426
5 Conclusion 428
References 428
Cannabinoids and Anxiety 433
1 Introduction 435
2 The Endocannabinoid System of the Brain 437
3 How to Study the Role of the Endocannabinoid System 440
3.1 Monitoring of Endocannabinoid Signaling 440
3.2 Attenuation of Endocannabinoid Signaling 441
3.3 Facilitation of Endocannabinoid Signaling 441
4 Animal Models of Fear and Anxiety 443
5 Role of Cannabinoids and Endocannabinoids in Fear and Anxiety - Animal Studies 445
5.1 Unconditioned Fear/Anxiety 445
5.1.1 Natural and Synthetic Cannabinoids 445
5.1.2 Enhancing the Levels of Endocannabinoids 446
5.1.3 Inactivation of CB1 Receptors 446
5.1.4 Intracerebral Injections 447
5.2 Conditioned Fear 447
6 Role of (Endo)Cannabinoids in Fear and Anxiety - Situation in Humans 449
7 The Endocannabinoid System in Fear and Anxiety - Theoretical and Practical Considerations 450
References 452
Pharmacological Therapy 455
Pharmacological Treatment of Generalized Anxiety Disorder 456
1 Clinical Features, Epidemiology and Burden of GAD 457
2 Response Rates to Initial Treatment in GAD 458
3 Prediction of Response to Pharmacological Treatment in GAD 461
4 Optimal Duration of Treatment in GAD 462
5 Management after Nonresponse to Initial Treatment in GAD 463
6 Tolerability of Current Treatments for GAD 465
7 Conclusions 466
References 466
Pharmacologic Treatment of Panic Disorder 471
1 Introduction 472
2 Clinical Assessment Before Treatment 472
3 Treatment Selection 473
3.1 Treatment Implementation 474
4 Pharmacologic Treatments 475
5 Mechanisms of Action 476
6 Serotonergic Agents 477
6.1 Efficacy of 5-HT and NE Reuptake Blockers 479
6.1.1 Tricyclic Antidepressants 479
6.2 Other Agents with 5-HT and NE Mechanisms 480
6.2.1 Benzodiazepines 480
6.3 Other Agents 481
7 Novel Treatment Approaches 481
7.1 Anxiolytic Drug Development 481
7.2 New Treatment Strategies 482
8 Conclusions 483
References 483
Pharmacotherapy of Social Anxiety Disorder 488
1 Introduction 489
2 Irreversible Inhibitors of Monoamine Oxidase 489
2.1 Phenelzine 489
3 Reversible Inhibitors of Monoamine Oxidase Type A 490
3.1 Moclobemide 490
3.2 Brofaromine 491
4 Benzodiazepines 491
5 Selective Serotonin Reuptake Inhibitors 491
5.1 Paroxetine 492
5.2 Fluvoxamine 492
5.3 Sertraline 493
5.4 Fluoxetine 494
5.5 Escitalopram 494
6 Serotonin and Noradrenalin Reuptake Inhibitors 495
6.1 Venlafaxine 495
7 Other Antidepressants 496
7.1 Nefazodone 496
7.2 Mirtazapine 496
8 Beta Blockers 496
9 Anticonvulsants 497
9.1 Gabapentin 497
9.2 Pregabalin 497
9.3 Levetiracetam 497
10 Atypical Antipsychotics 498
10.1 Olanzapine 498
10.2 Quetiapine 498
11 Other Agents 498
11.1 Buspirone 498
11.2 d-Cycloserine 498
12 Treatment Resistance and Augmentation 499
13 Discussion 499
References 500
Pharmacotherapy of Post-Traumatic Stress Disorder 505
1Introduction 506
2Antidepressants 507
2.1Selective Serotonin Reuptake Inhibitors (SSRIs) 507
2.2Serotonin Norephinephrine Reuptake Inhibitors (SNRIs) 510
2.3Tricyclic Antidepressants (TCAs) 511
2.4Monoamine Oxidase Inhibitors 512
2.5Other Antidepressants 513
3Anticonvulsants 514
4Atypical Antipsychotics 515
5Benzodiazepines and Other Hypnotics 516
6Antiadrenergic Agents 517
7Other Agents 519
8Conclusions 520
References 521
Pharmacological Treatment of Obsessive-Compulsive Disorder 526
1 Introduction 527
2 Serotonin Reuptake Inhibitors in the Treatment of OCD 528
2.1 Comparative Efficacy 528
2.2 Dose 529
2.3 Time to Response 530
2.4 Side Effects 530
2.5 Suicidality 531
2.6 Duration of Treatment 532
2.7 Drug Discontinuation Syndrome 532
2.8 The Role of Venlafaxine or Duloxetine in the Treatment of OCD 533
3 Limitations of Serotonin Reuptake Inhibitors in the Treatment of OCD 533
3.1 Partial Response to Serotonin Reuptake Inhibitors 534
3.1.1 Antipsychotic Augmentation 534
3.1.2 CBT Augmentation 535
3.1.3 Other Augmentation Strategies 535
3.2 Nonresponders to Serotonin Reuptake Inhibitors 535
4 Novel Medications in OCD 536
5 Conclusion 537
References 538
Index 543