Pharmacogenetics of Psychotropic Drugs

Cover Page......Page 1
Pharmacogenetics of Psychotropic Drugs......Page 3
Title Page......Page 5
ISBN 0521806178......Page 6
Contents......Page 7
Contributors......Page 10
Part I Introduction......Page 13
Introduction......Page 15
The rationale for psychopharmacogenetics......Page 16
Historical perspective......Page 17
Definition of terms......Page 18
Core issues in pharmacogenetic research design......Page 21
Definition and evaluation of the phenotype......Page 22
Interaction among multiple loci......Page 23
An age of optimism......Page 24
Pharmacogenetics of psychotropic drugs: an overview......Page 25
Conclusions......Page 27
REFERENCES......Page 28
Part II Clinical background and research design......Page 31
Introduction......Page 33
Heritability of psychotropic drug response......Page 34
Methodological issues in the pharmacogenetics of psychotropic drug response......Page 36
Limitations of case-control association studies......Page 38
From pharmacogenetics to pharmacogenomics......Page 41
Completion of the human genome sequence and identification of single nucleotide polymorphisms......Page 42
Developments in statistical genetic methodologies......Page 43
Conclusions......Page 44
REFERENCES......Page 45
OVERVIEW......Page 48
Epidemiological genetics......Page 49
Molecular genetics: candidate gene approach......Page 50
Consensus-based diagnostic classifications......Page 51
Alternative approaches......Page 52
Psychiatric nosology......Page 53
Karl Kahlbaum......Page 54
Emil Kraepelin......Page 55
Karl Kleist......Page 56
Kurt Schneider......Page 57
DCR Budapest–Nashville......Page 58
CODE-system......Page 59
Nosologic matrix......Page 60
REFERENCES......Page 62
Introduction......Page 69
Pharmacogenetics and variables affecting drug action......Page 71
Efficacy: a poor signal:noise ratio in clinical psychopharmacology......Page 72
Drug development: screening out pharmacogenetic differences......Page 73
Future psychiatric drug development: screening in pharmacogenetic differences......Page 75
Pharmacogenetic studies and existing drugs......Page 77
CYP2D6 as an example......Page 78
Efficacy as a difficult target for study in psychiatry......Page 79
Conclusions......Page 81
REFERENCES......Page 82
Introduction......Page 84
The pharmacogenetic trait: definition and methods of analysis......Page 85
How to define a phenotype in psychopharmacogenetics......Page 88
Association and linkage disequilibrium methods......Page 90
Polymorphic variants in the human genome......Page 91
Sample size required for candidate gene studies......Page 92
Methods of analysis: study design......Page 95
Conclusions......Page 98
REFERENCES......Page 99
Part III Molecular background......Page 105
Introduction......Page 107
Psychopharmacological drug response as a complex trait......Page 108
Variation of structure and expression of pharmacodynamic factors......Page 110
Serotonin receptors......Page 112
Serotonin transporter......Page 114
Monoamine oxidase......Page 116
Brain development and serotonin......Page 117
Mouse models and the emerging concept of developmental pharmacogenetics......Page 119
Regulatory genes of neurodevelopment......Page 123
Developmental specification and differentiation of serotonergic neurons......Page 124
Are epistatic interactions relevant to brain development?......Page 127
Conclusions......Page 129
REFERENCES......Page 131
Introduction......Page 139
Overview of post-transcriptional RNA processing......Page 140
RNA processing defects in psychiatric disorders......Page 141
The NMDA R1 subunit of ionotropic glutamate receptor......Page 143
The GABA-A receptor......Page 145
The dopamine…......Page 147
Potential mechanisms for splicing alterations......Page 149
Glutamate receptors......Page 150
The serotonin 2C receptor......Page 153
Potential mechanisms for editing alterations......Page 155
Conclusions......Page 157
REFERENCES......Page 159
Part IV Pharmacokinetics......Page 167
Introduction......Page 169
Phase I and phase II drug metabolism......Page 170
Physicochemical properties and nomenclature for cytochrome P-450s......Page 171
CYP2D6 polymorphism: a classical example of monogenic control in drug metabolism......Page 172
Relevance for the design and interpretation of genetic studies of complex diseases......Page 176
Intraindividual variations in drug metabolism and gene–environment interactions......Page 177
Dietary influence on intraindividual variability......Page 178
Drug–drug interactions and nutraceutical influences on drug metabolism......Page 179
Influence of aging on drug metabolism......Page 180
Influence of disease on variability in drug metabolism......Page 181
Genetic variability in drug metabolism and therapeutic drug monitoring......Page 182
Conclusions......Page 183
Acknowledgements......Page 185
REFERENCES......Page 186
Introduction......Page 193
Mianserin......Page 195
Mirtazapine......Page 197
Trimipramine......Page 198
Citalopram......Page 199
Fluoxetine......Page 201
Venlafaxine......Page 205
Achiral antidepressants with chiral metabolites: amitriptyline and nortriptyline......Page 206
Thioridazine......Page 208
Haloperidol......Page 211
Oxazepam......Page 212
Opioid substituents......Page 213
Conclusions......Page 214
REFERENCES......Page 215
Part V Specific psychotropic drugs and disorders......Page 227
OVERVIEW......Page 229
Clozapine......Page 230
What influences clinical response to antipsychotic medication?......Page 231
What is response to clozapine?......Page 232
Defining candidates genes: the pharmacology of clozapine and results of genetic analysis......Page 234
Dopamine D receptor......Page 236
Dopamine D receptor......Page 237
Dopamine D receptor......Page 238
Serotonin 5-HT receptors......Page 239
Serotonin…......Page 240
Serotonin 5-HT receptors......Page 241
Serotonin 5-HT receptors......Page 242
Histamine receptors......Page 243
Alpha-adrenoceptors......Page 244
Interaction between genes......Page 245
Conclusions......Page 246
REFERENCES......Page 247
Human evidence supporting a genetic basis for tardive dyskinesia......Page 257
Animal data supporting a genetic basis for tardive dyskinesia......Page 258
Association approach for locating actual genes involved......Page 259
Analytic strategies and phenotype definition......Page 260
Candidate gene studies of drug-induced tardive dyskinesia......Page 261
Dopamine D receptor gene......Page 262
Serotonin 2A receptor gene......Page 264
Serotonin 2C receptor gene......Page 266
Serotonin transporter gene......Page 267
Cytochrome P-450 2D6......Page 268
Manganese superoxide dismutase......Page 269
Conclusions......Page 270
REFERENCES......Page 273
Introduction......Page 279
The serotonin transporter......Page 281
Neurotransmitter metabolism......Page 285
Monoamine oxidase A......Page 286
Catechol-O-methyltransferase......Page 287
Conclusions......Page 288
REFERENCES......Page 291
Introduction......Page 295
Genetic predictors of the response to antidepressants in mood and anxiety disorders: the controversial role of the serotonin…......Page 296
The serotonin transporter gene and the antiobsessional response......Page 297
The serotonin transporter gene and antidepressant response......Page 299
Epidemiological and clinical features of antidepressant-induced mania......Page 302
Pharmacogenetics of antidepressant-induced mania......Page 303
Conclusions......Page 306
REFERENCES......Page 307
Introduction......Page 312
GABA, benzodiazepines, and anxiety......Page 314
Molecular biology of the GABA-A receptor......Page 315
Putative functions of the GABA-A receptor subunits......Page 318
Identification of the role of GABA-A subunits in anxiety, through molecular manipulation......Page 319
Studies of mutation of individual amino acids......Page 320
Possible interventions at the GAB-A receptor set-point......Page 321
Drug development: subtype selective ligands......Page 323
Future research......Page 324
REFERENCES......Page 325
Introduction......Page 332
Family and family-history studies of lithium response......Page 333
Lithium response as a phenotype......Page 337
Studies of lithium responders as a homogeneous subtype of bipolar disorder......Page 338
Studies comparing responders and nonresponders to lithium......Page 339
Other mood stabilizers......Page 340
REFERENCES......Page 341
Introduction......Page 345
The nature of genetic variation......Page 346
Genetic influences on the pharmacology of anticonvulsant drugs......Page 347
Hydantoins......Page 349
Carbamazepine......Page 352
Valproic acid......Page 353
Benzodiazepines......Page 354
Barbiturates......Page 356
Miscellaneous drugs......Page 358
Conclusions......Page 359
REFERENCES......Page 360
Introduction......Page 372
Pharmacogenetics of Alzheimer’s disease......Page 373
Cholinergic treatments......Page 375
Noncholinergic drugs......Page 379
REFERENCES......Page 381
Introduction......Page 384
Genetics of substance dependence: opiates, cocaine, and tobacco......Page 385
Heritability of substance dependence......Page 386
Pharmacodynamic effects: differing nature of ligand–receptor interaction by individual......Page 387
Pharmacogenetics and substance dependence in practice......Page 388
Opioid dependence: receptor/ligand interactions......Page 389
Cocaine dependence: cocaine-induced paranoia as a phenotype......Page 392
Tobacco dependence: CYP2A6 and therapeutic agents......Page 393
Issues of population genetics and variation by population group......Page 394
Conclusions......Page 395
REFERENCES......Page 396
Part VI Pharmacogenetics and brain imaging......Page 401
Introduction......Page 403
Alzheimer’s disease......Page 404
Side effects and schizophrenia......Page 405
Conclusions......Page 406
REFERENCES......Page 408
Part VII Industrial perspectives......Page 412
Introduction......Page 413
Current application of genomics to drug development......Page 415
Issues underlying application of genetic polymorphisms to drug development......Page 418
Phenotyping/genotyping drug metabolism......Page 421
Pharmacogenetics and drug toxicity......Page 423
Pharmacogenetic predictors of central nervous system drug response......Page 424
Prospective enrichment of trials through genotyping......Page 426
REFERENCES......Page 427
Complexity of the genetic component of the drug response......Page 432
SNP genotyping technologies......Page 434
Restriction endonuclease digestion......Page 435
Allele-specific ligation......Page 438
Denaturing high performance liquid chromatography......Page 440
TaqMan (5' exonuclease assay)......Page 441
Peptide nucleic acid hybridization probes......Page 442
Light-up probes......Page 443
Realtime polymerase chain reaction......Page 444
Conclusions......Page 445
REFERENCES......Page 446
Index......Page 451