Behavioral Neurobiology of Bipolar Disorder and its Treatment (eBook)

Preface 6
Acknowledgments 10
References 10
Acknowledgments 10
Contents 12
Contributors 14
Course and Outcome of Bipolar Disorder 18
1 Historical Legacies 19
2 The Course of BPD Prior to the Introduction of Modern Psychotropic Agents 19
3 Methodological Issues 20
4 Childhood and Adolescent Antecedents of BPD 21
5 The Onset of BPD: Age 22
5.1 Specific Age-Related Presentations 22
5.1.1 Postpartum BPD 22
5.1.2 Late-Onset BPD 22
6 The Onset of BPD: Polarity 23
7 Subtypes and Patterns of BPD Based on Course of Illness 24
7.1 Bipolar I and II Disorders 24
7.2 Rapid-Cycling Illness 24
7.3 Nature of the Cycle 24
7.4 Predominant Polarity 25
8 Duration and Outcome of Individual Episodes 26
9 Recurrence Rates and Clinical Outcomes 27
9.1 Retrospective or Cross-Sectional Studies 27
9.2 Prospective Studies 28
10 Predictors/Correlates of Recurrence 28
11 Other Outcomes 30
11.1 Disability 30
11.2 Death Rates 30
12 Conclusion 31
References 31
Genetics of Bipolar Disorder 36
1 Introduction 36
2 Genetic Epidemiology of BPD 37
2.1 Twin Studies 37
2.2 Family Studies 38
3 Molecular Genetics 38
3.1 Genetic Linkage and Candidate Gene Studies 38
3.2 Genome-Wide Association Studies 39
4 New Strategies in BPD Genetics Research 40
4.1 Redefining the Phenotype 40
4.2 Novel Molecular Tools 43
4.3 Novel Analytical Tools 44
5 Summary 44
References 44
Understanding Bipolar Disorder: The Epigenetic Perspective 48
1 Introduction 49
2 Concepts in Epigenetics 49
3 Bipolar Disorder: The Epigenetic Perspective 51
4 Discordance of Monozygotic Twins 52
5 Sexual Dimorphism 53
6 Parent-of-Origin Effects 54
7 Other Epigenetic Effects That May Be of Relevance to BPD 55
8 Experimental Approaches to Epigenetic and Epigenomic Studies of BPD 57
9 Pilot DNA Methylome Study in BPD 57
10 Methodological and Experimental Complexities in Studying Epigenetic Factors in Psychiatric Disease 58
11 Summary 59
References 60
Clinical Endophenotypes for Bipolar Disorder 67
1 Clinical Endophenotypes for Bipolar Disorder 68
2 Defining Endophenotypes 69
3 Evidence for Neurocognitive Endophenotypes for Bipolar Disorder 69
4 Evidence for Temperamental Endophenotypes for Bipolar Disorder 74
5 Conclusions 78
References 78
Strategies for the Development of Animal Models for Bipolar Disorder: New Opportunities and New Challenges 84
1 Introduction 85
2 Animal Models - Basics 85
3 A Short Summary of What We Have and Use Today 88
4 Development of Appropriate Tests 90
4.1 Developing Tests for Behavioral Domains of BPD 91
4.2 Models and Tests for Endophenotypes of Disease 92
5 Identifying the Best Species and the Best Strains 94
5.1 Model Animals Based on Strain Differences 94
5.2 Nontraditional Models 95
6 Conclusion 97
References 97
Partial Rodent Genetic Models for Bipolar Disorder 103
1 Introduction 104
2 Partial Models for Anhedonia and Depression (Table 1) 106
3 Partial Models for Mania and Excessive Behavioral Excitement (Table 2) 109
4 Partial Models for Affective Vulnerability or Resilience (Table 3) 113
5 Cyclicity 115
6 Closing Remarks 116
References 116
The Role of the Aminergic Systems in the Pathophysiology of Bipolar Disorder 121
1 Introduction 122
1.1 Neurobiological Methods 123
2 Serotonin 124
2.1 Cerebrospinal Fluid Studies 124
2.2 Postmortem Studies 125
2.3 5-HT Receptors and Transporters: PET Imaging Studies 125
2.4 Conclusion 126
3 Norepinephrine 127
3.1 Metabolite Studies 127
3.2 Tyrosine Hydroxylase in Locus Coeruleus NE Neurons 128
3.3 Genetics 128
3.4 Medication for BPD: Mood Stabilizers 128
3.5 Medication for BPD: Antidepressants 129
3.6 Conclusion 129
4 Dopamine 130
4.1 Cerebrospinal Fluid Studies 130
4.2 Pharmacological Studies 130
4.3 Neuroimaging Studies 131
4.4 Conclusion 131
5 Acetylcholine 132
5.1 Pupilometry and Medications in BPD 132
5.2 Cholinesterase Inhibitors 133
5.3 Conclusion 133
6 Conclusion 134
References 135
The Neurobiology of Bipolar Disorder: From Circuits to Cells to Molecular Regulation 141
1 Introduction 142
2 The Corticolimbic GABA System in Psychosis 142
3 Hippocampal Circuitry and Modulation by GABA Cells 143
4 Regulation of GAD67 Expression 144
5 The Role of Glutamate Receptors and Channels in GAD67 Regulation 144
6 Medication Effects in Bipolar Disorder 148
7 Conclusions 149
References 150
Signal Transduction Pathways in the Pathophysiology of Bipolar Disorder 153
1 Introduction 154
2 Signal Transduction Pathway Abnormalities in BPD 154
3 Receptor Types 155
3.1 G-Protein-Coupled Receptors 155
3.2 Glutamatergic Neurotransmission 156
3.3 Tyrosine Receptor Kinase 157
4 Second Messenger Targets 158
4.1 Cyclic Adenosine Monophosphate and Protein Kinase A Pathway 158
4.2 Phosphoinositide Pathway (PLC: IP3-Ca++-CAMK DAG-PKC)
4.3 The Regulation of Glycogen Synthase Kinase-3 by Protein Kinase B (Akt) and Wnt 163
4.4 Arachidonic Acid 165
5 Transcription Factors 166
5.1 beta-Catenin 167
5.2 cAMP Response Element Binding Protein 167
5.3 Heat Shock Transcription Factor-1 and Activator Protein-1 169
6 Conclusion 169
References 170
Synaptic Plasticity in the Pathophysiology and Treatment of Bipolar Disorder 180
1 Introduction 181
2 Synaptic Plasticity in Psychoneurobiology 182
3 Synaptic Plasticity Is a Common Target of the Mood Stabilizers Lithium and Valproate 183
4 Modulation of Synaptic Plasticity by the Monoaminergic Systems: Serotonin, Norepinephrine, and Dopamine 184
4.1 Serotonin 184
4.2 Norepinephrine 185
4.3 Dopamine 186
5 Brain-Derived Neurotrophic Factor Is a Key Modulator of Synaptic Plasticity 186
6 Neural and Synaptic Plasticity During Chronic Stress 187
7 Proinflammatory Cytokines in Regulating Synaptic Plasticity: Potential Implications for Mood Disorders 188
7.1 Regulation of Synaptic Plasticity by Tumor Necrosis Factor-a 188
7.2 Regulation of Synaptic Plasticity by IL-1 189
7.3 Regulation of Synaptic Plasticity by IL-6 190
8 Brain Imaging Studies of Patients with BPD Demonstrate Changes in Neural Plasticity in the Brain Circuits Associated with Mood Disorders 190
9 Synaptic Plasticity Models for Mood Disorders and Future Directions 191
References 192
Mitochondrial Dysfunction and Bipolar Disorder 199
1 Introduction 200
2 What are Mitochondria? 201
3 Mitochondrial DNA 201
4 Relationship with the Endoplasmic Reticulum 202
5 The Foundations of the Mitochondrial Dysfunction Hypothesis 203
5.1 Possible Role of Maternal Inheritance 203
5.2 Comorbidity with Mitochondrial Diseases 204
5.3 Mechanism of Action of Mood Stabilizers 204
5.4 Magnetic Resonance Spectroscopy 205
5.5 Mitochondrial DNA Mutations 205
5.6 Gene Expression Analysis 206
5.7 Animal Models 206
6 Future Directions 207
References 208
Neuroimaging and Neuropathological Findings in Bipolar Disorder 213
1 Introduction 214
2 The Subgenual ACC 214
3 The Rostral ACC 217
4 The Dorsal ACC 219
5 The Orbital frontal Cortex 220
6 BA 9 of the Dorsolateral Prefrontal Cortex 220
7 The Insula 223
8 The Thalamus 224
9 The Striatum 224
10 The Hippocampus 225
11 The Amygdala 228
12 Conclusion 229
References 229
Functional Neuroimaging Research in Bipolar Disorder 238
1 Introduction 239
2 Ventral Prefrontal Cortex 241
2.1 Studies of Research Participants at Rest 241
2.2 Studies of Research Participants During Task Performance 242
2.2.1 Processing of Emotional Stimuli 242
2.2.2 Performance of Cognitive Tasks 243
3 Amygdala 245
4 Hippocampus 246
5 Basal Ganglia and Thalamus 246
6 Neuroimaging Studies in Adolescents with BPD 247
7 Functional Connectivity 250
8 Functional Neuroimaging, Genes, and Treatment 251
9 Conclusion 251
References 252
Sleep and Circadian Rhythm Abnormalities in the Pathophysiology of Bipolar Disorder 257
1 Introduction 258
2 Rhythm Abnormalities in Bipolar Disorder 259
2.1 Sleep/Wake Rhythms 259
2.2 Rest/Activity Rhythms 260
2.3 Chronotype 260
2.4 Social Rhythms 261
2.5 Biological Rhythms 262
3 Treatments for Bipolar Disorder Targeting Rhythm Abnormalities 263
3.1 Interpersonal and Social Rhythm Therapy 263
3.2 Family-Focused Treatment 264
3.3 Cognitive-Behavioral Therapy 264
3.4 Light Therapy, Dark Therapy, Sleep Deprivation 266
3.5 Pharmacologic Treatments for Bipolar Disorder 266
4 Conclusions 267
References 267
Pharmacological Treatments for Bipolar Disorder: Present Recommendations and Future Prospects 273
1 Introduction 274
2 Early, Accurate Diagnosis of BPD 275
3 Assessing Published Studies in BPD 275
4 Practice Guidelines 277
5 Tactics in Selecting and Implementing Therapies 278
6 Specific Components of Treatment 280
6.1 Mania 280
6.1.1 Combination Regimens for Mania 280
6.1.2 Mixed Manic States 281
6.1.3 Psychotherapy 282
6.2 Depression 282
6.3 Maintenance Therapy 283
7 Tactics for Adverse Effects 283
7.1 Insulin Resistance, Diabetes, and Obesity 284
7.2 Thyroid Function 285
7.3 Renal Function 285
7.4 Cognitive Adverse Effects 286
7.5 Agitation/Tremor/Akathisia 286
7.6 Stevens-Johnson Syndrome 286
8 Circadian Rhythm Pattern 287
9 Vocational Initiatives 288
10 Moving Toward and Managing Health 288
11 Toward a Fresh Mindset on Drug Development, Early Phase Testing, and Design of Registration Studies for BPD 289
References 291
Nonpharmacotherapeutic Somatic Treatments for Bipolar Disorder (ECT, DBS, rTMS) 294
1 Electroconvulsive Therapy 295
1.1 Treatment of Acute Mania 295
1.1.1 Efficacy Relative to Other Treatments 295
1.1.2 Efficacy in Mania Compared with Other Affective States 296
1.1.3 The Optimal Form of ECT in Treating Mania 296
1.2 Treatment of Bipolar Depression 297
1.2.1 Efficacy of ECT Relative to Antidepressant Medications 298
1.2.2 Comparative Efficacy in Bipolar and Unipolar Depression 298
1.2.3 Risk of Switching to Mania 298
1.3 Treatment of Mixed Affective States 300
1.4 Maintenance ECT in BPD 301
1.5 Concurrent Medications 301
1.5.1 Lithium 302
1.5.2 Anticonvulsants 302
2 Transcranial Magnetic Stimulation 303
2.1 rTMS in the Treatment of Acute Mania 304
2.2 rTMS in the Treatment of Bipolar Depression 305
2.3 rTMS: Switching into Mania and Other Adverse Effects 306
3 Vagus Nerve Stimulation, Stereotactic Ablation, and Deep Brain Stimulation 306
4 Concluding Remarks 307
References 308
Potential Novel Therapeutics for Bipolar Disorders 312
1 Introduction 313
2 The Opioid Neuropeptide System 314
2.1 Kappa Opioid Receptors 315
3 The Glutamatergic System 316
3.1 NMDA Antagonists 316
3.2 AMPA Potentiators 318
3.3 Metabotropic Glutamate Receptors 318
3.4 Glutamatergic Modulators: Riluzole 319
3.5 Cytidine 320
4 The Purinergic System 320
5 The Cholinergic System 321
5.1 The Muscarinic System 321
5.2 The Nicotinic Acetylcholine Receptor System 322
6 The Melatonergic System 323
7 Drugs with Multiple Targets and Potential Relevance in BPD 324
7.1 Modafinil 324
7.2 Uridine (RG2417) and Triacetyluridine (RG2133) 325
8 Oxidative Stress and Bioenergetics 325
8.1 N-Acetyl Cysteine 325
8.2 Creatine 326
9 The AA Cascade 326
10 Intracellular Signaling Pathways and Targets Worthy of Further Study in BPD 327
10.1 Glycogen Synthase Kinase-3 327
10.2 The PKC Signaling Cascade 328
11 Final Remarks 329
References 329
Bipolar Disorder: A Neurobiological Synthesis 339
1 Genetics 340
2 The Neurobiological Evidence 342
3 Conclusions 346
References 347
Index 349