Anxiety Disorders: Pathophysiology and Pharmacological Treatment

312 Pages·2002·6.83 MB·English

by  Dr. Gérard Emilien

Gerard Emilien
Cecile Durlach
Ulla lepola
Timothy Dinan
Anxiety Disorders
Pathophysiology and Pharmacological Treatment
Springer Basel AG
Authors
Dr. Gerard Emilien Prof. limothy Dinan
127 rue Hen ri Prou Department of Pharmacology and Therapeutics
78340 Les Clayes Sous Bois University College Cork
France Ireland
Dr. Ulla Ma~atta Lepola Dr. Cecile Durlach
Kuopion Psykiatripalvelu Oy 23 Rue Raynouard
Psychiatric Research Clinic of Kuopio 75016 Paris
Asemakatu 46 France
FIN-70110 Kuopio
Finland
A CIP catalogue record for this book is available from the Library of Congress, Washington D.C., USA
Deutsche Bibliothek Cataloging-in-Publication Data
Anxiety disorders : pathophysiology and pharmacological treatment I
written by Gerard Emilien .... -Basel ; 80ston ; Berlin : Birkhăuser, 2002
ISBN 978-3-0348-9460-9 ISBN 978-3-0348-8157-9 (eBook)
DOI 10.1007/978-3-0348-8157-9
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© 2002 Springer Basel AG
Originally published by Birkhiiuser Verlag, Basel, Swilzerland in 2002
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Cover design: Micha Lotrovsky, Therwil, Swilzerland
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Contents
Glossary......................................................................... xi
Introduction ..................................................................... xv
Chapter 1:
Normal and pathological anxiety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1 What is anxiety? .... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.1 Anxiety in children ....................................................... 5
1.2 Anxiety in the elderly .................................................... 7
1.3 Personality and anxiety .................................................. 9
1.4 Cognitive aspects of anxiety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
1.4.1 Gray neurophysiological model of anxiety .............................. 13
1.5 Comorbidity of anxiety disorders ........................................ 14
1.6 Anxiety scales. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
2 Relevance of laboratory research on anxiety disorders .................. 17
3 Genetic factors and brain imaging. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
4 Management ............................................................ 19
5 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
Chapter 2:
Biological basis of anxiety and strategies for pharmacological innovation 31
1 Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
2 Neurobiology of anxiety disorders ....................................... 32
2.1 Generalised anxiety disorder. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
2.2 Panic disorder. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
2.3 Social phobia ............................................................ 37
2.4 Post-traumatic stress disorder ........................................... 37
2.5 Obsessive-compulsive disorders ......................................... 38
3 Recent development and future anxiolytics ............................. 38
3.1 5-HT receptors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
3.2 GABA receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
3.3 Neuropeptide (CCK, CRF, NPY and NK) receptors ...................... 43
3.4 Glutamatergic pathways................................................. 46
vi Table of contents
3.5 Opioid receptors......................................................... 47
3.6 Neurosteroids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
3.7 Equilibrium between GABA-benzodiazepine and other receptors....... 49
3.8 Use of mutant mice...................................................... 51
4 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
Chapter 3:
Generalised anxiety disorder .................................................... 67
1 Introduction. . . . . . . . . . . . . . . . . . . . . . . . . .. . .. . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . 67
2 Diagnostic ............................................................... 68
3 The phenomenon of worry .............................................. 69
4 Neurobiology ............................................................ 70
4.1 Imaging studies .......................................................... 72
4.2 Genetics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
5 Physiopathology ......................................................... 73
6 Epidemiology and natural course ........................................ 74
7 Treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
7.1 Psychological............................................................ 74
7.2 Biofeedback.............................................................. 75
7.3 Pharmacological. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
7.3.1 Benzodiazepines......................................................... 76
7.3.2 Buspirone................................................................ 76
7.3.3 Venlafaxine .............................................................. 77
7.3.4 SSRls..................................................................... 77
7.3.5 Tricyclics ................................................................. 77
7.3.6 Other drugs.............................................................. 78
7.3.7 Algorithm for treatment................................................. 78
8 Methodology for clinical investigation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
9 Discussion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
Chapter 4:
Social phobia .................................................................... 89
1 Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
2 Diagnosis and comorbidity .............................................. 93
2.1 Subtypes................................................................. 93
2.2 Differential diagnosis .................................................... 94
2.3 Comorbidity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
2.4 Epidemiology............................................................ 97
2.5 Natural history. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98
2.6 Childhood and adolescence versus adult social phobia.................. 98
3 Pathophysiology ......................................................... 99
3.1 Genetic. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99
3.2 Neurophysiology ......................................................... 100
3.3 Neuroimaging ........................................................... 101
3.4 Environment ............................................................. 101
Table of contents vii
3.5 Gender and cultural differences ......................................... 102
4 Treatments ............................................................... 103
4.1 Psychological. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 103
4.2 Pharmacological. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 106
4.3 Comparison, combination of drug versus cognitive-behavioral therapy .. 107
4.4 Algorithm for treatment ................................................. 112
5 Methodology of clinical investigations .................................. 113
5.1 Rating scales ............................................................. 113
5.2 Self-assessment questionnaires .......................................... 114
5.3 Clinician/computer-administered scales ................................. 115
5.4 Health Outcome Assessments ........................................... 119
5.5 Assessment of recovery .................................................. 120
6 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 120
Chapter 5:
Panic disorder ................................................................... 133
1 Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 133
2 Diagnosis and aetiology ................................................. 134
2.1 Comorbidity ............................................................. 136
2.2 Epidemiology ............................................................ 136
3 Pathophysiology ......................................................... 138
3.1 Autonomic and central nervous system dysfunctions ................... 139
3.2 Brain imaging ............................................................ 142
3.3 Respiratory function and carbon dioxide sensitivity ..................... 142
3.4 Genetic .................................................................. 143
3.5 Impact on cognitive processes ........................................... 143
4 Treatments ............................................................... 144
4.1 Psychological. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 144
4.2 Pharmacological. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 145
4.2.1 Benzodiazepines ......................................................... 145
4.2.2 Tricyclic antidepressants ................................................. 145
4.2.3 SSRls ..................................................................... 149
4.2.4 Other treatments ........................................................ 150
4.2.5 Algorithm for treatment ................................................. 150
5 Methodology for clinical investigation ................ . . . . . . . . . . . . . . . . . .. 153
5.1 Psychometric scales ...................................................... 153
5.2 Assessing response and remission ....................................... 157
6 Discussion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 157
Chapter 6:
Obsessive-compulsive disorder .................................................. 173
1 Introduction .............................................................. 173
2 Diagnostic ............................................................... 173
2.1 Comorbidity ............................................................. 176
2.2 Epidemiology ............................................................ 176
viii Table of contents
2.3 Natural history ........................................................... 178
3 Physiopathology ......................................................... 178
3.1 Neurobiology ............................................................ 178
3.2 Brain imaging ............................................................ 179
3.3 Genetics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 180
3.4 Cognitive dysfunctions .................................................. 181
4 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 182
4.1 Psychological treatment ................................................. 182
4.2 Pharmacological treatment .............................................. 183
4.2.1 Clomipramine ............................................................ 183
4.2.2 SSRI and the 5-HT receptors ............................................ 183
4.2.3 Addition of atypical neuroleptics ........................................ 184
4.2.4 Course of therapy ....................................................... 184
4.2.5 Children .................................................................. 184
4.2.6 Some cultural differences in treatment practice ......................... 185
5 Methodology for clinical investigation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 187
5.1 Psychometric scales ...................................................... 188
6 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 188
Chapter 7:
Posttraumatic stress disorder .................................................... 199
1 Introduction .............................................................. 199
2 Epidemiology ............................................................ 201
3 Comorbidity ............................................................. 202
4 Physiological and neurological abnormalities associated with PTSD ..... 203
4.1 Physiological abnormalities .............................................. 204
4.2 Neurobiology and brain abnormalities ................................... 206
5 Cognitive dysfunction associated with PTSD ............................ 208
5.1 Assessment of PTSD ..................................................... 208
5.2 Attentional bias: The emotional Stroop test ............................. 211
5.3 Memory ................................................................. 212
6 Treatment of PTSD ...................................................... 214
6.1 Psychotherapeutic approach ............................................. 214
6.1.1 Exposure therapy ........................................................ 215
6.1.2 Anxiety management programs ......................................... 216
6.1.3 Cognitive therapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 217
6.1.4 Eye movement and desensitisation reprocessing ........................ 217
6.2 Biofeedback .............................................................. 218
6.3 Pharmacological approach ............................................... 218
6.3.1 Tricyclics ................................................................. 218
6.3.2 Selective serotonin reuptake inhibitors .................................. 219
6.3.3 Anticonvulsants .......................................................... 221
6.3.4 ~-blocker and <X2-agonist ................................................ 221
6.3.5 <X1-antagonists ........................................................... 222
6.3.6 Buspirone ................................................................ 222
Table of contents ix
6.3.7 Other drugs ............................................................. 222
6.3.8 New research strategy in pharmacotherapy of PTSD ................... 224
7 Discussion ............................................................... 224
Chapter 8:
Phobic disorders ................................................................. 239
1 Introduction ............................................................. 239
2 Epidemiology ............................................................ 241
3 Genetics ................................................................. 241
4 Treatment ............................................................... 242
4.1 Psychological ............................................................ 242
4.2 Biofeedback ............................................................. 242
4.3 Pharmacological . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 243
5 Discussion ............................................................... 243
Chapter 9:
Laboratory models of anxiety ................................................... 249
1 Introduction ............................................................. 249
2 Biological animal models ................................................ 251
2.1 GABAergic transmission and benzodiazepine receptor function ........ 251
2.2 5-HT receptor knockouts ............................................... 253
2.3 Corticotropin-releasing hormone mutation and CRH-receptor
knockouts ............................................................... 253
2.4 Genetically selected alcohol-preferring rats ............................. 255
3 Behavioural animal models .............................................. 255
3.1 Anxiety .................................................................. 255
3.1.1 Elevated plus-maze ..................................................... 255
3.1.2 Elevated T-maze ........................................................ 258
3.1.3 The holeboard test ...................................................... 260
3.1.4 Stress-induced hyperthermia ............................................ 260
3.1.5 Fear potentiated startle ................................................. 261
3.1.6 Burying behaviour test .................................................. 261
3.1.7 Stretched attend posture test ........................................... 262
3.1.8 Light-dark transition test ................................................ 262
3.1.9 Social interaction ........................................................ 263
3.1.10 Ultrasonic distress vocalisation .......................................... 264
3.1.11 A primate model ........................................................ 264
3.2 Panic disorder ........................................................... 265
3.2.1 Periaqueductal gray model .............................................. 265
3.2.2 The mouse defence test battery ........................................ 266
3.2.3 Other new behavioural models ......................................... 266
3.3 Generalised anxiety disorder ............................................ 267
3.4 Obsessive-compulsive disorder ......................................... 267
3.5 Posttraumatic stress disorder ............................................ 268
3.6 Effects ofthe antidepressants in the models ............................ 268
X Table of contents
4 Human models ..............' . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 269
4.1 Some models of anxiety .................................................. 269
4.1.1 The video-recorded Stroop colour word test ............................. 269
4.1.2 Fear potentiated startle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 269
4.2 Generalised anxiety disorder ............................................. 270
4.3 Panic disorder ............................................................ 270
5 Issues relevant to some non-benzodiazepine anxiolytics ................. 270
5.1 5-HT receptors ........................................................... 270
5.2 Cholecystokinin receptors ................................................ 271
6 Discussion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 271
Chapter 10:
Discussion and perspectives ..................................................... 287
Future perspectives ............................................................. .
Index ............................................................................ 295
Glossary
ACTH AdrenocorticotropiC hormone
ANF Atrial natriuretic factor
APA American Psychiatric Association
APD Avoidant personality disorder
AQ Avoidance questionnaire
ASI Anxiety sensitivity inventory
BDZ Benzodiazepine
BIS Behavioural inhibition system
BIU Behavioural inhibition to the unfamiliar
BPRS Brief psychiatric rating scale
BSPS Brief social phobia scale
cAMP Cyclic adenosine monophosphate
CAPS Clinician administered PTSD scale
CBF Cerebral blood flow
CCK Cholecystokinin
CCK4 Cholecystokinin tetrapeptide
CCSQ Confidence in coping strategies questionnaire
CFS Conditioned fear stress
CGI Clinical global impressions
CHRNA4 Neuronal nicotinic acetylcholine receptor a4 gene
CISD Critical incident stress debriefing
CNS Central nervous system
CNV Contingent negative variation
CPP Comprehensive panic profile
CRF Corticotropin-releasing factor
CRH Corticotropin-releasing hormone
CSF Cerebrospinal fluid
CSQ Coping strategies questionnaire
DA Dopamine
DES Dissociative experience scale
xi