Table of Contents

Preface 1 xiii

Preface 2 xv

A view from Esteve xix

Dedication and Acknowledgements xxi

List of Contributors xxiii

Glossary xxix

Volume 1

1 Depressive Disorders 1

1.1 Introductory and Basic Aspects 3
Neurobiology of Mood Disorders
Luz Romero, Ana Montero, Begoña Fernández and José M. Vela

1.1.1 Definition of mood disorders, impact on a global scale and unmet needs 3

1.1.2 Causes and associations in mood disorders: genetics and pharmacogenetics 10

1.1.3 Pathogenesis of mood disorders 14

1.1.4 Concluding remarks 33

References 35

1.2 Clinics 51
Clinical Aspects of Depressive Disorder
Rosario Pérez-Egea, Victor Pérez, Dolors Puigdemont and Enric Alvarez

1.2.1 Introduction 51

1.2.2 Classification 52

1.2.3 Epidemiology 61

1.2.4 Physiopathology 63

1.2.5 Treatment of affective disorders 68

References 104

1.3 Pharmacology 111
Pharmacotherapy of Depression
Begoña Fernández, Luz Romero and Ana Montero

11.3.1 Introduction 111

1.3.2 Current antidepressant treatments 112

1.3.3 New strategies for antidepressant treatments 116

1.3.4 Concluding remarks 131

References 132

1.4 Experimental Research 141
Modeling Human Depression by Animal Models
Ana Montero, Begoña Fernández and Luz Romero

1.4.1 Introduction 141

1.4.2 Types of validity 142

1.4.3 Animal models of depression 145

1.4.4 Some concluding remarks 160

References 162

1.5 Chemistry
Marketed Drugs and Drugs in Development
Jörg Holenz, José Luis Díaz and Helmut Buschmann

173

1.5.1 Summary of drug classes 173

1.5.2 Tricyclic and tetracyclic antidepressants 173

1.5.3 Serotonergic agents 193

1.5.4 Noradrenaline reuptake inhibitors 231

1.5.5 Monoamine oxidase inhibitors 233

1.5.6 Miscellaneous agents 239

1.5.7 Compounds launched in single countries 248

1.5.8 New opportunities for marketed drugs 249

1.5.9 Summary of antidepressants in development 249

References 261

2 Schizophrenia and Other Psychoses 297

2.1 Introductory and Basic Aspects 299
Current Status and Challenges in Schizophrenia Research
Francesc Artigas

2.1.1 Introduction 299

2.1.2 Clinical diagnosis and assessment of schizophrenia 300

2.1.3 Epidemiology 306

2.1.4 Course of schizophrenia 307

2.1.5 Brain pathology in schizophrenia 308

2.1.6 Pathogenesis and pathophysiology of schizophrenia 316

2.1.7 Concluding remarks 326

References 327

2.2 Clinics 335
Schizophrenia: A Clinical Review
Salvador Ros and Francisco Javier Arranz

2.2.1 Introduction 335

2.2.2 Background 336

2.2.3 Epidemiology 341

2.2.4 General semiology 341

2.2.5 Positive symptoms in schizophrenia 342

2.2.6 Negative symptoms in schizophrenia 345

2.2.7 Cognitive alterations in schizophrenia 347

2.2.8 Characteristics of cognitive deterioration in schizophrenia 350

2.2.9 Methods to evaluate cognitive deterioration in schizophrenia 356

2.2.10 Affective symptoms in schizophrenia 358

2.2.11 Schizophrenia and suicide 360

2.2.12 Onset and states 365

2.2.13 Etiopathogeny 367

2.2.14 Prognosis 373

2.2.15 Schizophrenia therapy 375

References 378

2.3 Pharmacology 389
Pharmacotherapy of Schizophrenia
Analía Bortolozzi, Llorenç Díaz-Mataix and Francesc Artigas

2.3.1 Antipsychotic drugs: introduction 389

2.3.2 Atypical Antipsychotics: introduction 401

2.3.3 Other major investigational approaches 425

2.3.4 Concluding remarks: challenges in drug discovery 429

References 432

2.4 Experimental Research 449
Modeling schizophrenia in experimental animals
Pau Celada, Anna Castañé, Albert Adell and Francesc Artigas

2.4.1 Introduction 449

2.4.2 Neurophysiology of schizophrenia 450

2.4.3 Pharmacological models of schizophrenia 453

2.4.4 Neurodevelopmental models 464

2.4.5 Genetic models 468

2.4.6 Other animal models 473

2.4.7 Concluding remarks 474

References 475

2.5 Chemistry 491
Marketed Drugs and Drugs in Development
Antonio Párraga, Jörg Holenz and Helmut Buschmann

2.5.1 Summary of drug classes 491

2.5.2 Typical antipsychotics 494

2.5.3 Atypical antipsychotics 549

2.5.4 Drugs in development 579

References 586

Volume 2

3 Anxiety 617

3.1 Introductory and Basic Aspects

3.1.1 Definition and classification of anxiety disorders 619
Francisca López-Ríos, Serafín Gómez-Martín and Antonio Molina-Moreno

References 643

3.1.2 Epidemiology of anxiety disorders 645
Flor Zaldívar-Basurto and José M. García-Montes

References 662

3.1.3 Etiology of Anxiety 667
Margarita Moreno, Ginesa López-Crespo and Pilar Flores

References 678

3.1.4 Anxiety disorders and drug abuse 685
Diana Cardona-Mena, Margarita Moreno and Pilar Flores

References 701

3.1.5 Neurobiology of anxiety (I): Panic disorder, posttraumatic stress disorder, social phobia and obsessive–compulsive disorder 709
Lola Roldán-Tapia, Ginesa López-Crespo, Francisco Antonio Nieto-Escámez and Diana Cardona-Mena

References 743

3.1.6 Neurobiology of anxiety (II): Childhood anxiety, generalized anxiety disorder and mixed anxiety–depressive disorder 761
Francisco Antonio Nieto-Escámez, Ginesa López-Crespo, Lola Roldán-Tapia and Fernando Cañadas-Pérez

References 785

3.1.7 Consequences of anxiety on memory processes (I): Introductory and clinical aspects 803
Fernando Cañadas-Pérez, Francisco Antonio Nieto-Escámez, Lola Roldán-Tapia and Ginesa López-Crespo

References 821

3.1.8 Consequences of anxiety on memory processes (II): Neurobiological aspects 831
Francisco Nieto-Escámez, Fernando Cañadas-Pérez, Lola Roldán-Tapia and Fernando Sánchez-Santed

References 864

3.2 Clinics 881
Clinical Aspects of Anxiety
Blanca Gutiérrez and Jorge Cervilla

3.2.1 Conceptual introduction 881

3.2.2 Panic disorder 882

3.2.3 Generalized anxiety disorder 885

3.2.4 Phobic anxiety disorders 888

3.2.5 Obsessive-compulsive disorder 890

3.2.6 Conclusion 892

References 893

3.3 Pharmacology 895
Pharmacology of Anxiety
José Manuel Baeyens

 3.3.1 Introduction 895

3.3.2 Drugs used in treatment of anxiety disorders: an overview 896

3.3.3 Generalized anxiety disorder (GAD) 902

3.3.4 Social anxiety disorder (SAD) or social phobia 905

3.3.5 Simple or specific phobia 908

3.3.6 Panic disorder (PD) 908

3.3.7 Posttraumatic stress disorder (PTSD) 911

3.3.8 Obsessive-compulsive disorder (OCD) 914

References 918

3.4 Experimental Research 923
Modeling Human Anxiety by Animal Models
Enrique Portillo and José Miguel Vela

3.4.1 General concepts on animal models 923

3.4.2 General aspects of human anxiety 925

3.4.3 Animal anxiety 926

3.4.4 Potential issues in animal models of anxiety 937

3.4.5 Conclusions: Implication for drug discovery 940

References 942

3.5 Chemistry 951
Marketed Drugs and Drugs in Development
Mónica García-López, Susana Yenes, Helmut Buschmann and Antoni Torrens

3.5.1 Summary of drug classes 951

3.5.2 Benzodiazepines 951

3.5.3 Serotonergic drugs 999

3.5.4 GABAergic agents 1006

3.5.5 Dopaminergic agents 1011

3.5.6 Serotonin reuptake stimulants 1017

3.5.7 5-HT2 receptor antagonists 1019

3.5.8 -adrenoceptor antagonists 1021

3.5.9 Glucocorticoid receptor antagonists 1026

3.5.10 GAT-1 inhibitors 1029

3.5.11 Calcium channel blockers 1032

3.5.12 No-described mechanism of action 1039

3.5.13 Drugs in development 1051

References 1069

4 Attention Deficit and Hyperactivity Disorders 1089

4.1 Introductory and Basic Aspects 1091
Neurobiological aspects of Attention Deficit and Hyperactivity Disorders
Javier Burgueño, Rafael Franco and Francisco Ciruela

4.1.1 Definition and introductory clues 1091

4.1.2 Etiology of ADHD 1095

References 1100

4.2 Clinics 1105
Attention Deficit Hyperactivity Disorder: Clinical and Therapeutic Facts
Francisco Javier Arranz and Salvador Ros

4.2.1 Introduction 1105

4.2.2 Epidemiology 1108

4.2.3 Etiology 1114

4.2.4 Pathophysiology 1118

4.2.5 Clinical features 1122

References 1146

4.3 Pharmacology 1155
Pharmacology: Targets of Drug Action
Francisco Ciruela, Rafael Franco and Javier Burgueño

4.3.1 Neurobiological evidence for ADHD as an organic phenomenon 1155

4.3.2 Neurochemistry of ADHD: Neurotransmitter imbalance 1156

References 1177

4.4 Chemistry 1183
Marketed Drugs and Drugs in Development
Jörg Holenz, José Luis Díaz and Helmut Buschmann

4.4.1 Summary of drug classes 1183

4.4.2 Drugs in development 1192

References 1194

Index 1197

About the Author

The editors all work for the Spanish-based pharmaceutical company Esteve, a world leader in neuropharmaceuticals.
Helmut Buschmann is the research director of Esteve, in charge of the discovery and development of new active substances for a variety of neurological disorders. He was formerly the head of research at Gruenenthal, a Germany-based pharma company that also specialized in neuropharmaceuticals. During his time at Gruenenthal, he published a widely acclaimed book on analgesics that pioneered the integrated approach followed also in his most recent book.