Psychopharmacogenetics

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Dr. Swanand S Pathak

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Psychopharmacogenetics

  1. 1. Psychopharmacogenomicsconceptual reality or awaiting dream? Dr. Swanand S Pathak MBBS MD DACM IDCR Dept. of Pharmacology JNMC, Sawangi drswanandp@yahoo.co.in
  2. 2. Part I ( basic concepts ) What is pharmacogenomics Difference between the pharmacogenetics and pharmacogenomics. What is psychopharmacogenomics Historical aspects of pharmacogenomics What are SNPs Concept of CYP enzymes and genetics Part II ( neuropsychopharmacogenomics) Psychopharmacogenomics in relation to antideparessants , atipsyachotics and mood stabilizers. Psychopharmacogenomics in relation with the drug development in psychiatry
  3. 3. Part IBASIC CONCEPTS
  4. 4. Genomics OM – COMPLETE GENE GENES GENOME ICS – STUDY GENOMICS
  5. 5. Pharmacogenomics Drugs + genome = health benefit
  6. 6.  Pharmacogenetics : study of the effect of single gene on the response of various drugs Pharmacogenomics : study of the effect of multiple genes on the response of various drugs
  7. 7. Psychopharmacogenomics :Study of the effects of variations in multiplegenes on the response of drugs used inpsychiatry and the psychiatric disorders.
  8. 8. NEED ?
  9. 9. Variability in Drug ResponseDisease Drug Class Rate of Poor responseAsthma Beta-agonists 40-75%Hypertension Various 30%Solid Cancers Various 70%Depression SSRIs, tricyclics 20-40%Diabetes Sulfonylureas, others 50%Arthritis NSAIDs, COX-2 inhibitors 30-60%Schizophrenia Various 25-75%
  10. 10.  ( lieberman et al N Engl J Med 2005) Clinical antipsychotic trials of intervention effectiveness (CATIE) : 18 months 74% discontinued : lack of efficacy or tolerability.
  11. 11. CONVENTIONAL DRUG DEVELOPMENT APPROACH
  12. 12. ScenarioAll patients with same diagnosis 1 Non-responders and toxic responders 2 Responders and patients not predisposed to toxicity
  13. 13. This can be improved by Giving the Right Drug At Right Dose To the Right Patient At the Right TimePatient specific selection of medication and their dosage
  14. 14. “Pharmacogenomics”
  15. 15. Pharmacogenomics holds the promise that drugs might one day be tailor-made for individuals and adapted to each persons own genetic makeup.Environment, diet, age, lifestyle, and state of health all can influence a persons response to medicines, but understanding an individuals genetic makeup is thought to be the key to creating personalized drugs with greater efficacy and safety.
  16. 16. HISTORY
  17. 17. Important Facts Human genome = 22 chromosome pairs and 1 pair of sex chromosomes Functional unit of the genome = gene 2% of genes code for proteins, remainder is structural for DNA Entire genome = 3 billion DNA pairs, with ~30,000 protein coding genes
  18. 18. Allele An allele is one member of a pair that makes up a gene 2 same alleles are homozygous (one allele on each part a pair of chromosomes) 2 different alleles are heterozygous
  19. 19. • DNA sequence of all human beings is 99.9% identical • Our DNAs differ by 0.1%. • Does it make a difference ? YES !0.1% difference translates into 3 millionseparate “spelling” differences in agenome of 3 billion bases
  20. 20. Genetic Polymorphism? A genetic polymorphism is any mutant or variant gene that occurs with a frequency of more than 1% in the normal population Denoted by : *
  21. 21. POLYMORPHISM TYPES SNP INSERTIONS DELETIONS• Missense • Missense • Missense• Nonsense • Nonsense • Nonsense• Frameshift • Frameshift • Frameshift Go to
  22. 22. PolymorphismsSingle nucleotide polymorphisms (SNP) ……..G G T A A C T T G …... ……..G G C A A C T T G …... • Most common • Incidence 1 per 300 - 600bp
  23. 23. NormalMissense
  24. 24. NormalNonsense
  25. 25. NormalFrameshift
  26. 26. Deleted area Before After deletion deletion
  27. 27. Duplicated area Before duplication After duplication
  28. 28. ? MOSTIMPORTANT
  29. 29. PolymorphismsSingle nucleotide polymorphisms (SNP) ……..G G T A A C T T G …... ……..G G C A A C T T G …... • Most common • Incidence 1 per 300 - 600bp
  30. 30. CYP 450
  31. 31. Cytochrome P450 enzyme system terminology CYP2C9 *2 “ CYP” - P450 for all mammalian species “ 2” - family (17 - 14 human) “ C” - subfamily (42 in humans) “ 9” - enzyme/gene (55 genes) *2: -Allele pattern
  32. 32. 23 SETS OF HUMAN CHROMOSOMES
  33. 33. Chromosome 10q24.2CYP2C9 CYP2C9 P M
  34. 34. Impact of CYP2C9*2 genetic polymorphism on enzymatic activity Nucleotide # 430 C G TCYP2C9*1 Exon 3 Amino acid #144 Arg Normal enzymatic activity Nucleotide # 430 T G T CYP2C9*2 Exon 3 9 Amino acid #144 Cys Reduced enzymatic activity
  35. 35. What do the CYPs do? Drug metabolism throughout the body Activate drugs Detoxify substances and activate non-toxic substances into toxic substances
  36. 36. Proportion of Drugs Metabolized by CYP Enzymes CYP3A4/5 36% CYP1A1/2 11% CYP2A6 3% CYP2B6 3% CYP2E1 4% CYP2D6 CYP2C8/9 CYP2C19 16% 19% 8%
  37. 37. Part II Neuropsychopharmacogenomics
  38. 38. Consequences of polymorphisms Drug metabolism Drug transport Disease Polymorphisms Receptorsusceptibility sensitivity ADR
  39. 39. Disease susceptibility Alzheimer’s disease : Apo E
  40. 40. Drug metabolism
  41. 41. CYP2D6 Vs Starting dose of nortriptylineNormal CYP2D6 : 150 mg/dayMutant CYP2D6 : 10-20 mg/day
  42. 42. CYP2C9 Vs Phenytoin maintenance doseGenotype Mean dose (mg/d)CYP2C9 *1/*1 314 mg/dCYP2C9 *1/*2 193 mg/dCYP2C9 *2/*3 150 mg/d(Source: Pharmacogenetics, 2001, 11, 287-291)
  43. 43. Why diazepam metabolism is slower in Asians compared to Caucasians?Because Asians have high frequency of mutant alleles CYP2C19 Genotype Allele Diazepam t1/2 caucasians CYP2C19 *1/*1 20 hours FM Asians CYP2C19 *2/*2 84 hours PM
  44. 44. Transport
  45. 45. Function of P-gp The human MDR1 encodes amembrane P-glycoprotein thatmediates ATP-dependent efflux. P-gp resides in the plasma membraneand functions as an efflux transporter ofa wide variety of natural compoundsand dugs
  46. 46. Receptor sensitivity
  47. 47. Receptor Sensitivity/Effect Subjects with Gly 389 have reducedβ1 receptor geneArg389Gly sensitivity to beta-blockersSer49Gly Subjects with Gly 49 have increased sensitivity to beta-blockers
  48. 48. Beta-1 Adrenergic Receptor Codon 49 SerGly Codon 389 ArgGlyPodlowski, et al. J Mol Med 2000;78:90.
  49. 49. Adverse drug reaction
  50. 50. CYP2C9 polymorphism and phenytoin toxicity Ataxia, nystagmus, drowsiness, gingival hyperplasia Genotype : CYP2C9*3/*3
  51. 51. This girl may develop side effects to  Warfarin  Glibenclamide  Acenocoumarol  Tolbutamide  Losartan  Ibuprofen  Irbesartan  Flurbiprofen  Glipizde  Diclofenac All metabolized by CYP2C9 enzyme
  52. 52. CYP2D6 Polymorphisms and Psychiatric Drug Response Increased rate of adverse effects in poor metabolizers due to increased plasma concentrations of drug:  Fluoxetine (Prozac®) death in child attributed to CYP2D6 poor metabolizer genotype  Side effects of antipsychotic drugs occur more frequently in CYP2D6 poor metabolizers  CYP2D6 poor metabolizers with severe mental illness had more adverse drug reactions, increased cost of care, and longer hospital stays
  53. 53. Pharmacogenomics Information in the Published Literature Zineh I et al. Ann Pharmacother. 2006; 40: 639-44
  54. 54. AntidepressantsAntipsychoticsMood stabilizers
  55. 55. Antidepressants 119 pharmacogenomic studies reported CYP 2D6 , CYP 2C19 PM : more side effects UM : more therapeutic effect Association with 5 HTR2A , GRIK2 genes.
  56. 56. Mood stabilizers 102 pharmacogenomic studies reported Association with GRIA2, ODZ4 genes decrease efficacy
  57. 57. Antipsychotics 84 pharmacogenomic studies reported EPF1 ,NOVA 1 : antipsychotic induced parkinsonism ZNF202 : extrapyramidal side effects
  58. 58. Psychopharmacogenomics and Drug Development
  59. 59. • An investigative drug showed NO statistically significant effect when given to 400 Alzheimer’s patients,• A clinically significant response was elicited when patients were stratified according to ApoE subtype (Richard et al., 1997).
  60. 60. TacrineNo statistical significant response
  61. 61. Genotyped Tacrine ApoE1 ApoE2No statistical significant response ApoE3 ApoE4
  62. 62. ApoE1 ApoE2 Stratify the patients according to genotypes ApoE4 ApoE3
  63. 63. ApoE1 Tacrine No statisticalApoE2 significant responseApoE3
  64. 64. Tacrine Statistical significant responseApoE4
  65. 65. Pre-clinical Gene Expression Toxicogenomics  Predict toxicity of candidate compounds  Identify mechanisms of toxicity Identify potential biomarkers for toxicity or efficacy for future clinical studies
  66. 66. Phase I studiesExclude or include specific patientsNormalize genotype frequencies
  67. 67. Phase II/III studies Identify genetically-defined groups with more pronounced or rapidly progressing disease Exclude/include at-risk individuals Stratify studies based on genotypes  Clinical response  Risk of adverse events Where appropriate, develop drugs for specific groups
  68. 68. FDA and Pharmacogenomics FDA published: “Draft Guidance for Industry: Pharmacogenomic Data Submission” in 2003. (currently under revision) Set criteria for Voluntary Genomic Data Submission (VGDS) (http://www.fda.gov/cder/guidance/5900dft.pdf)
  69. 69. What are the anticipated benefits of Pharmacogenomics?
  70. 70. Individualized MedicinesPharmaceutical companies will be able tocreate drugs based on the proteins,enzymes, and RNA molecules associatedwith genes and diseases.This will facilitate drug discovery and allowdrug makers to produce a therapy moretargeted to specific diseases. This accuracynot only will maximize therapeutic effectsbut also decrease damage to nearby healthycells.
  71. 71. Cost Effectiveness ? • Phase III trial - CNS product -4500 patients- Cost per patients $ 8000 - $ 12,000• Eliminate 10% (Approx 450 subjects) of trial population (Non-responders) Using Pharmacogenomic Save $ 3,60,000 - $5,40,000. (Murphy , Pharmacogenetics, 2000; 10:1-7)
  72. 72. Some ethical IssuesCould the development of medicines forspecific groups of the population excludeothers?Will the development of unprofitable, butdesirable, medicines be neglected?Who will have access to genetic informationand databases?
  73. 73. Research Issues Translating• Narrower target population could exclude those who might also benefit from therapies• Evaluating therapies in smaller, targeted trials might miss critical, albeit rare, adverse drug events
  74. 74. Social IssuesHealth Horoscope  Will I develop this disease ten years from now? • Can I indulge in unhealthy habits (e.g., smoking, junk food, not exercising, etc.) if I don’t have a particular disease susceptibility?
  75. 75. Patient requires Treatment Examination by the PhysicianGenomic testing Traditional investigations EXPERT SYSTEM Decision making by Physician, assisted by an Expert System (interactive interpretation) Prescribes individualized drug treatment
  76. 76. Tools for prediction
  77. 77. Roche AmpliChip: FDA-Approved CYP2D6 , CYP 2C19
  78. 78. The Next Diagnostic Chips?Additional diagnostics are needed:General: CYP2C9; CYP3A5; CYP2B6;MDR-1; UDP Glucuronosyltransferases(UGTs);N-acetyltransferases (NATs)Oncology: thiopurine methyltransferase(TMPT);Thymidilate synthase; dihydropyrimidine
  79. 79. Personalized Medicine: “when?” SMART CARD In your wallet by 2025? Praveen khairkar 97236407611 GENOME Or maybe by 2050? (Confidential)Opinion: This sort of card would initially (~2025?) include mostlyinformation related to drug metabolizing enzymesAround ~2050 it might include an entire individual genome(or at least, few millions SNPs..)
  80. 80. Science or Science Fiction ?Unrealistic projections for 2025:Most medicines will be prescribedaccording to patient genotypingGenomics would allow full insight intothe biological basis of complex humandiseases
  81. 81. PGx: Science and Science FictionRealistic projections for 2025 Genotyping would allow far smaller rates of adverse reactions for most drugs In several medical disciplines, genomics would allow far better medical treatment (oncology; psychiatry; neurology)
  82. 82. “Hereis mysequence”
  83. 83. TiPS 24:122-126 (2003)
  84. 84. Part I What is pharmacogenomics Difference between the pharmacogenetics and pharmacogenomics. What is psychopharmacogenomics Historical aspects of pharmacogenomics What are SNPs Concept of CYP enzymes and genetics Part II Psychopharmacogenomics in relation to antideparessants , atipsyachotics and mood stabilizers. Psycchopharmacogenomics in relation with the drug development in psychiatry
  85. 85. Conceptual reality or awaiting dream ? Definitely a conceptual reality For grass root patients and practitioners … there is still a long long way to go …to fulfill the dream …
  86. 86. Acknowledgements Dr. Praveen Khairkar Dr. Sushil Verma Dr. Aniket Shukla Dr. Adithan Google and Wikipedia

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