Table of Contents

Preface xiii

About the Companion Website xv

1 Introduction to Neuropsychopharmacology 1

1.1 Overview 1

1.2 A Brief Overview of the Anatomy and Function of the Brain 2

1.2.1 The Brainstem 2

1.2.2 The Metencephalon 3

1.2.3 Diencephalon 4

1.2.4 The Telencephalon 5

1.2.5 The Cerebral Ventricles and Cerebrospinal Fluid 7

1.3 Important Neurotransmitters 7

1.3.1 GABA and GABA Receptors 7

1.3.2 Glutamate and Glutamate Receptors 10

1.4 Central Nervous System Stimulant and Depressant Drugs 11

1.5 Central Nervous System (CNS) Stimulant Drugs 13

1.5.1 Psychomotor Stimulants 13

1.5.2 Analeptic Drugs 19

1.6 Depressant Drugs 21

1.6.1 Benzodiazepines 21

1.6.2 Other Depressant Drugs 23

1.7 Genetics 23

1.8 Electroencephalography and Imaging Techniques 24

1.8.1 Electroencephalography 24

1.8.2 X-Rays 24

1.8.3 Computed Tomography 24

1.8.4 Positron Emission Tomography 25

1.8.5 Magnetic Resonance Imaging 25

1.8.6 Functional MRI 25

1.9 Diagnostic Criteria for Mental Disorders 25

1.10 Animals Models for CNS Disorders 26

1.11 Summary 27

2 Parkinson’s Disease 28

2.1 Overview 28

2.2 Historical Background 28

2.3 Epidemiology 29

2.4 Primary Clinical Features 29

2.5 Secondary Clinical Features 30

2.6 Parkinson’s Disease and the Extrapyramidal System 31

2.7 Neurotransmission in the Extrapyramidal System and Parkinson’s Disease 33

2.7.1 Modulation of the Direct and Indirect Pathways 35

2.8 Causes of Parkinson’s Disease 36

2.8.1 Genes and Parkinson’s Disease 37

2.8.2 Environmental Neurotoxins 39

2.8.3 Oxidative Stress 41

2.9 Summary 42

2.10 Pharmacotherapy for Parkinson’s Disease 42

2.10.1 L-DOPA (L-Dihydroxyphenylalanine) 43

2.10.2 L-DOPA Treatment 44

2.10.3 Adverse Effects of L-DOPA 44

2.10.4 Adverse Effects after Long-Term Treatment 46

2.10.5 Alternative Formulations of L-DOPA and Other Pharmacological Agents 48

2.11 Nonmotor Symptoms of Parkinson’ Disease and the Development of a New Hypothesis 53

2.12 Pharmacological and Nonpharmacological Strategies for Treatment of Other Motor and Nonmotor Symptoms of Parkinson’s Disease 55

2.13 Other Nonpharmacological Methods of Treating Parkinson’s Disease 56

2.13.1 Lesions of the Globus Pallidus or Subthalamic Nucleus 56

2.13.2 Neurostimulation 57

2.13.3 Brain Grafts 57

2.14 Possible Future Strategies to Treat Parkinson’s Disease 58

2.14.1 Stem Cell Therapy 58

2.14.2 Gene Therapy 58

2.15 Early Diagnosis for Treatment of Parkinson’s Disease 59

2.16 Summary and Conclusions 59

3 Memory, Dementia and Alzheimer’s Disease 61

3.1 Overview 61

3.2 Learning and Memory 61

3.2.1 Temporal Stages of Learning, Memory and Recall 62

3.2.2 Where are STM and LTM Stored in the Brain? 67

3.3 Overview of Dementia 69

3.4 Alzheimer’s Disease (AD) 71

3.4.1 Clinical Symptoms of Alzheimer’s Disease 72

3.4.2 Neuropathological Changes 74

3.4.3 Molecular Pathology 74

3.4.4 Staging of Alzheimer’s Disease 80

3.4.5 Onset of Alzheimer’s Disease 80

3.4.6 Neurochemical Changes in Alzheimer’s Disease 82

3.4.7 Pharmacotherapy of Alzheimer’s Disease 85

3.4.8 Future Pharmacological Strategies in the Treatment of Alzheimer’s Disease 88

3.4.9 Cardiovascular Disease 91

3.4.10 Conclusions 91

3.5 Summary 92

4 Epilepsy 93

4.1 Overview 93

4.2 Background 94

4.3 Classification and Types of Epilepsy 94

4.3.1 Focal Seizures 94

4.3.2 Generalized Seizures 95

4.3.3 Epilepsy Syndromes 97

4.3.4 Epidemiology 98

4.4 Underlying Causes of Epilepsy 98

4.5 Epileptic Mechanisms 99

4.5.1 Electrophysiological Mechanisms 99

4.5.2 Mechanisms Underpinning Drug Treatment of Epilepsy 100

4.6 Pharmacotherapy 101

4.6.1 Valproate (Valproic Acid and Sodium Valproate) 101

4.6.2 Phenytoin 105

4.6.3 Carbamazepine 106

4.6.4 Ethosuximide 107

4.6.5 Gabapentin 107

4.6.6 Pregabalin 108

4.6.7 Lamotrigine 109

4.6.8 Tiagabine 109

4.6.9 Topiramate 110

4.6.10 Levetiracetam 110

4.6.11 Retigabine 111

4.6.12 Zonisamide 111

4.6.13 Benzodiazepines 112

4.6.14 Barbiturates 112

4.7 Vagal Nerve Stimulation 113

4.8 Summary 113

5 Attention Deficit Hyperactivity Disorder 115

5.1 Overview 115

5.2 Background to ADHD 116

5.3 Diagnostic Criteria for ADHD 118

5.4 ADHD and Comorbidity 119

5.5 Epidemiology 120

5.6 Aetiology of ADHD 120

5.6.1 Genetic Factors 120

5.6.2 Environmental Factors 121

5.7 The Pathophysiology of ADHD 122

5.7.1 The Prefrontal Cortex, Executive Function and ADHD 122

5.7.2 Frontocortical-Striatal Networks and ADHD 126

5.8 The Biochemical Hypothesis of ADHD 130

5.9 Executive Functional Skills, Neurodevelopment and ADHD 132

5.10 Summary of the Pathophysiology of ADHD 135

5.11 Management of ADHD 135

5.11.1 Pharmacotherapy 136

5.11.2 Nonpharmacological Management of ADHD 142

5.12 Summary and Conclusions 144

6 Affective Disorders 1: Depression 147

6.1 Outline 147

6.2 Emotion, Mood and Affective Disorders 148

6.3 Background to Depression 149

6.4 Clinical Features of Major Depressive Disorder 150

6.4.1 Subtypes of Depressive Disorders 150

6.5 Epidemiology 152

6.6 Causes of Depression 153

6.6.1 Genetic Influences 153

6.6.2 Biochemical Hypotheses of Depression 154

6.7 Stress, Learned Helplessness and Depression 163

6.7.1 Stress and MDD 164

6.7.2 What is Stress? 164

6.7.3 Stress and Depression 166

6.7.4 Brain Derived Neurotropic Factor, Neurotropic Effects and Depression 167

6.7.5 Genetics, Stress and Depression 168

6.7.6 Early-Life Stress, Depression and Epigenetics 169

6.7.7 Depression and Inflammation 171

6.7.8 Depression and Glutamate 171

6.7.9 Depression and Physical Diseases 171

6.8 Drug Treatment of Depression 172

6.8.1 Overview 172

6.8.2 Types of Antidepressant Drug 174

6.8.3 Possible Future Drugs for MDD 186

6.9 Nonpharmacological Treatments for Depression 187

6.9.1 Electroconvulsive Therapy 187

6.9.2 Transcranial Magnetic Stimulation 188

6.9.3 Vagus Nerve Stimulation 189

6.9.4 Phototherapy (Light Therapy) 189

6.9.5 Deep Brain Stimulation 190

6.9.6 Cognitive Behavioural Therapy 190

6.9.7 Interpersonal Therapy 191

6.9.8 Behavioural Therapy 192

6.9.9 Mindfulness-Based Cognitive Therapy 192

6.10 Summary 192

7 Affective Disorders 2: Bipolar Disorder 194

7.1 Outline 195

7.2 Background to Bipolar Disorder 195

7.3 Clinical Features of Bipolar Disorder and Diagnostic Criteria 196

7.3.1 Symptoms of Mania 196

7.3.2 Symptoms of Hypomania 197

7.3.3 Symptoms of Depression 197

7.3.4 Categories of Bipolar Disorder 197

7.3.5 Rapid Cycling 197

7.3.6 Mixed Features 197

7.3.7 Cyclothymia 198

7.3.8 Suicide 198

7.3.9 Course of Illness 198

7.4 Epidemiology 198

7.5 Cause of Bipolar Disorder 199

7.5.1 Genetic Factors 199

7.5.2 Environmental Factors 199

7.5.3 Neurobiology of Bipolar Disorder 199

7.6 Management of Bipolar Disorder 201

7.6.1 Pharmacotherapy 201

7.6.2 Drugs Used in the Treatment of Bipolar Disorder 204

7.7 Pregnancy and Bipolar Disorder 208

7.8 Psychological Treatments 208

7.8.1 Psychoeducation 208

7.8.2 Family-Focused Treatment 209

7.8.3 Cognitive Behavioural Therapy 209

7.8.4 Interpersonal and Social Rhythm Therapy 209

7.8.5 Lifestyle Changes 210

7.9 Summary and Conclusions 210

8 Anxiety Disorders 211

8.1 Overview 211

8.2 Background 212

8.3 Anxiety Disorders and Diagnostic Criteria 212

8.3.1 Generalized Anxiety Disorder 212

8.3.2 Social Anxiety Disorder 213

8.3.3 Panic Attack and Panic Disorder 214

8.3.4 Agoraphobia 215

8.3.5 Others Types of Anxiety Disorders 216

8.4 Neurobiology of Anxiety Disorders 216

8.4.1 Fear and the Amygdala 216

8.4.2 Anatomy and Circuitry of the Amygdala 217

8.4.3 Physiological Responses to Fear-Eliciting Stimuli 217

8.4.4 Conditioned Fear Response 220

8.4.5 Conditioned Fear Extinction 223

8.5 Worry 224

8.6 Are there Other Anxiety Circuits? 225

8.7 Neurotransmitters and Anxiety Disorders 225

8.8 Management of Anxiety Disorders 226

8.8.1 Pharmacotherapy 226

8.8.2 Psychosocial Therapies 232

8.9 Summary and Outcomes 234

9 Sleep and Sleep Disorders 236

9.1 Overview 236

9.2 Introduction 237

9.3 Physiology of Sleep 238

9.3.1 Stages of Sleep 238

9.3.2 The Ascending Reticular Activating System 240

9.3.3 Slow Wave Sleep Mechanisms 242

9.3.4 Rapid Eye Movement Sleep Mechanisms 245

9.4 Sleep Disorders 246

9.4.1 Insomnia 246

9.4.2 Hypersomnia or Hypersomnolence 254

9.5 Summary and Conclusions 257

10 Schizophrenia 259

10.1 Overview 259

10.2 Background 260

10.3 Clinical Features of Schizophrenia 264

10.3.1 Phases of Schizophrenia 264

10.3.2 Diagnostic Criteria for Schizophrenia 265

10.3.3 Violence, Self-Harm and Suicide 265

10.3.4 General Physical Health and Mortality 266

10.4 Epidemiology 266

10.5 Pathology 266

10.6 Aetiology 267

10.6.1 Genetics of Schizophrenia 267

10.6.2 Environmental Risk Factors 268

10.7 Developmental Hypothesis of Schizophrenia 270

10.8 Biochemical Hypotheses 270

10.8.1 Dopamine and the Dopamine Hypothesis of Schizophrenia 270

10.8.2 The Mesolimbic System and Schizophrenia 273

10.8.3 The Mesocortical System and Schizophrenia 273

10.8.4 Glutamate, GABA and Dopamine: A Revised Hypothesis of Schizophrenia 274

10.9 Management of Schizophrenia 277

10.9.1 Pharmacotherapy 277

10.9.2 Nonpharmacological Management of Schizophrenia 288

10.10 Summary and Conclusions 288

11 Drug Abuse and Addiction 290

11.1 Outline 290

11.2 Background 291

11.3 Neurobiology of Substance Abuse and Addiction 293

11.3.1 The Mesolimbic Reward Systems and Addictive Drugs 293

11.3.2 Extensions of the Hypothesis 298

11.3.3 Transition from Hedonic Actions to Habits to Compulsions 300

11.3.4 Summary 301

11.4 Risk Factors 301

11.4.1 Environmental Factors 301

11.4.2 Genetic Factors 302

11.5 Management of Addiction 302

11.5.1 Alcohol 306

11.5.2 Heroin 307

11.6 Summary 308

References 310

Index 327

About the Author

Ivor S. Ebenezer, School of Pharmacy and Biomedical Sciences, University of Portsmouth, UK