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Psychopharmacogenomics
conceptual reality or awaiting dream?




           Dr. Swanand S Pathak
          MBBS MD DACM IDCR
           Dept. of Pharmacology
              JNMC, Sawangi
          drswanandp@yahoo.co.in
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
Part I


BASIC CONCEPTS
Genomics
   OM – COMPLETE

   GENE

   GENES

   GENOME

   ICS – STUDY

   GENOMICS
Pharmacogenomics



   Drugs + genome = health benefit
   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
Psychopharmacogenomics :

Study of the effects of variations in multiple
genes on the response of drugs used in
psychiatry and the psychiatric disorders.
NEED ?
Variability in Drug Response

Disease         Drug Class    Rate of Poor response

Asthma          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%
   ( lieberman et al N Engl J Med 2005)

   Clinical antipsychotic trials of intervention
    effectiveness (CATIE) : 18 months

   74% discontinued : lack of efficacy or tolerability.
CONVENTIONAL DRUG DEVELOPMENT APPROACH
Scenario
All patients with same diagnosis


                                   1    Non-responders
                                          and toxic
                                         responders




                     2
                                       Responders and patients
                                       not predisposed to toxicity
This can be improved by
   Giving the Right Drug
         At Right Dose
        To the Right Patient
        At the Right Time

Patient specific selection of medication and their dosage
“Pharmacogenomics”
Pharmacogenomics holds the promise that drugs might one day be
  tailor-made for individuals and adapted to each person's own
                            genetic makeup.


Environment, diet, age, lifestyle, and state of health all can influence
       a person's response to medicines, but understanding an
   individual's genetic makeup is thought to be the key to creating
         personalized drugs with greater efficacy and safety.
HISTORY
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
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
• 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 million
separate “spelling” differences in a
genome of 3 billion bases
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 : *
POLYMORPHISM TYPES


     SNP       INSERTIONS     DELETIONS


• Missense     • Missense     • Missense
• Nonsense     • Nonsense     • Nonsense
• Frameshift   • Frameshift   • Frameshift




                                             Go to
Polymorphisms

Single 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
Normal




Missense
Normal




Nonsense
Normal




Frameshift
Deleted area




               Before      After
               deletion   deletion
Duplicated area




                    Before
                  duplication

                                  After
                                duplication
? MOST
IMPORTANT
Polymorphisms

Single 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
CYP 450
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
23 SETS OF HUMAN CHROMOSOMES
Chromosome 10q24.2




CYP2C9                        CYP2C9




            P     M
Impact of CYP2C9*2 genetic polymorphism on enzymatic activity




  Nucleotide # 430       C    G T

CYP2C9*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
What do the CYPs do?
 Drug metabolism throughout the
  body
 Activate drugs

 Detoxify substances and activate

  non-toxic substances into toxic
  substances
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%
Part II

         Neuro
psychopharmacogenomics
Consequences of polymorphisms

             Drug metabolism     Drug transport




  Disease            Polymorphisms          Receptor
susceptibility                             sensitivity



                    ADR
Disease susceptibility



   Alzheimer’s disease : Apo E
Drug metabolism
CYP2D6 Vs Starting dose
       of nortriptyline


Normal CYP2D6 :   150 mg/day
Mutant CYP2D6 :   10-20 mg/day
CYP2C9 Vs Phenytoin maintenance dose


Genotype             Mean dose (mg/d)

CYP2C9 *1/*1         314 mg/d
CYP2C9 *1/*2         193 mg/d
CYP2C9 *2/*3         150 mg/d

(Source: Pharmacogenetics, 2001, 11, 287-291)
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
Transport
Function of P-gp
  The human MDR1 encodes a
membrane      P-glycoprotein that
mediates ATP-dependent efflux.

 P-gp resides in the plasma membrane
and functions as an efflux transporter of
a wide variety of natural compounds
and dugs
Receptor sensitivity
Receptor                  Sensitivity/Effect
                    Subjects with Gly 389 have reduced
β1 receptor gene
Arg389Gly          sensitivity to beta-blockers

Ser49Gly           Subjects with Gly 49 have increased
                   sensitivity to beta-blockers
Beta-1 Adrenergic Receptor
                   Codon 49 SerGly
                                          Codon 389
                                          ArgGly




Podlowski, et al. J Mol Med 2000;78:90.
Adverse drug reaction
CYP2C9 polymorphism and phenytoin toxicity




  Ataxia, nystagmus, drowsiness, gingival hyperplasia

        Genotype : CYP2C9*3/*3
This girl may develop side effects to

    Warfarin               Glibenclamide
    Acenocoumarol          Tolbutamide
    Losartan               Ibuprofen
    Irbesartan             Flurbiprofen
    Glipizde               Diclofenac

   All metabolized by CYP2C9 enzyme
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
Pharmacogenomics Information in
    the Published Literature




     Zineh I et al. Ann Pharmacother. 2006; 40: 639-44
Antidepressants
Antipsychotics
Mood stabilizers
Antidepressants
   119 pharmacogenomic studies reported

   CYP 2D6 , CYP 2C19

   PM : more side effects

   UM : more therapeutic effect
   Association with 5 HTR2A , GRIK2
    genes.
Mood stabilizers

   102 pharmacogenomic studies reported

   Association with GRIA2, ODZ4 genes
    decrease efficacy
Antipsychotics

   84 pharmacogenomic studies reported

   EPF1 ,NOVA 1 : antipsychotic induced
    parkinsonism

   ZNF202 : extrapyramidal side effects
Psychopharmacogenomics
          and
    Drug Development
• 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).
Tacrine


No statistical significant response
Genotyped




             Tacrine                         ApoE1
                                             ApoE2
No statistical significant response          ApoE3

                                             ApoE4
ApoE1                                                   ApoE2



         Stratify the patients according to genotypes




 ApoE4                                                   ApoE3
ApoE1




        Tacrine      No statistical

ApoE2             significant response




ApoE3
Tacrine
                         Statistical
                  significant response




ApoE4
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
Phase I studies




Exclude or include specific patients
Normalize genotype frequencies
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
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)
What are the anticipated benefits of
      Pharmacogenomics?
Individualized Medicines

Pharmaceutical companies will be able to
create drugs based on the proteins,
enzymes, and RNA molecules associated
with genes and diseases.

This will facilitate drug discovery and allow
drug makers to produce a therapy more
targeted to specific diseases. This accuracy
not only will maximize therapeutic effects
but also decrease damage to nearby healthy
cells.
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)
Some ethical Issues

Could the development of medicines for
specific groups of the population exclude
others?

Will the development   of unprofitable, but
desirable, medicines   be neglected?

Who will have access to genetic information
and databases?
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
Social Issues
Health 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?
Patient requires Treatment

             Examination by the Physician



Genomic testing                         Traditional
                                      investigations

                  EXPERT SYSTEM


     Decision making by Physician, assisted by an
      Expert System (interactive interpretation)


        Prescribes individualized drug treatment
Tools for prediction
Roche AmpliChip: FDA-Approved
     CYP2D6 , CYP 2C19
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
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 mostly
information related to drug metabolizing enzymes

Around ~2050 it might include an entire individual genome
(or at least, few millions SNPs..)
Science or Science Fiction ?
Unrealistic projections for 2025:

Most medicines will be prescribed
according to patient genotyping

Genomics would allow full insight into
the biological basis of complex human
diseases
PGx: Science and Science Fiction

Realistic 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)
“Hereis my
sequence”
TiPS 24:122-126 (2003)
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
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 …
Acknowledgements
   Dr. Praveen Khairkar
   Dr. Sushil Verma
   Dr. Aniket Shukla
   Dr. Adithan
   Google and Wikipedia
Psychopharmacogenetics

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Psychopharmacogenetics

  • 1. Psychopharmacogenomics conceptual reality or awaiting dream? Dr. Swanand S Pathak MBBS MD DACM IDCR Dept. of Pharmacology JNMC, Sawangi drswanandp@yahoo.co.in
  • 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
  • 4. Genomics  OM – COMPLETE  GENE  GENES  GENOME  ICS – STUDY  GENOMICS
  • 5.
  • 6. Pharmacogenomics  Drugs + genome = health benefit
  • 7. 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
  • 8. Psychopharmacogenomics : Study of the effects of variations in multiple genes on the response of drugs used in psychiatry and the psychiatric disorders.
  • 10. Variability in Drug Response Disease Drug Class Rate of Poor response Asthma 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%
  • 11. ( lieberman et al N Engl J Med 2005)  Clinical antipsychotic trials of intervention effectiveness (CATIE) : 18 months  74% discontinued : lack of efficacy or tolerability.
  • 13. Scenario All patients with same diagnosis 1 Non-responders and toxic responders 2 Responders and patients not predisposed to toxicity
  • 14. This can be improved by Giving the Right Drug At Right Dose To the Right Patient At the Right Time Patient specific selection of medication and their dosage
  • 16. Pharmacogenomics holds the promise that drugs might one day be tailor-made for individuals and adapted to each person's own genetic makeup. Environment, diet, age, lifestyle, and state of health all can influence a person's response to medicines, but understanding an individual's genetic makeup is thought to be the key to creating personalized drugs with greater efficacy and safety.
  • 18.
  • 19.
  • 20. 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
  • 21.
  • 22. 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
  • 23.
  • 24. • 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 million separate “spelling” differences in a genome of 3 billion bases
  • 25. 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 : *
  • 26. POLYMORPHISM TYPES SNP INSERTIONS DELETIONS • Missense • Missense • Missense • Nonsense • Nonsense • Nonsense • Frameshift • Frameshift • Frameshift Go to
  • 27. Polymorphisms Single 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
  • 31. Deleted area Before After deletion deletion
  • 32. Duplicated area Before duplication After duplication
  • 34. Polymorphisms Single 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
  • 36. 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
  • 37. 23 SETS OF HUMAN CHROMOSOMES
  • 39. Impact of CYP2C9*2 genetic polymorphism on enzymatic activity Nucleotide # 430 C G T CYP2C9*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
  • 40. What do the CYPs do?  Drug metabolism throughout the body  Activate drugs  Detoxify substances and activate non-toxic substances into toxic substances
  • 41. 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%
  • 42. Part II Neuro psychopharmacogenomics
  • 43. Consequences of polymorphisms Drug metabolism Drug transport Disease Polymorphisms Receptor susceptibility sensitivity ADR
  • 44. Disease susceptibility  Alzheimer’s disease : Apo E
  • 46. CYP2D6 Vs Starting dose of nortriptyline Normal CYP2D6 : 150 mg/day Mutant CYP2D6 : 10-20 mg/day
  • 47. CYP2C9 Vs Phenytoin maintenance dose Genotype Mean dose (mg/d) CYP2C9 *1/*1 314 mg/d CYP2C9 *1/*2 193 mg/d CYP2C9 *2/*3 150 mg/d (Source: Pharmacogenetics, 2001, 11, 287-291)
  • 48. 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
  • 50. Function of P-gp The human MDR1 encodes a membrane P-glycoprotein that mediates ATP-dependent efflux. P-gp resides in the plasma membrane and functions as an efflux transporter of a wide variety of natural compounds and dugs
  • 52. Receptor Sensitivity/Effect Subjects with Gly 389 have reduced β1 receptor gene Arg389Gly sensitivity to beta-blockers Ser49Gly Subjects with Gly 49 have increased sensitivity to beta-blockers
  • 53. Beta-1 Adrenergic Receptor Codon 49 SerGly Codon 389 ArgGly Podlowski, et al. J Mol Med 2000;78:90.
  • 55. CYP2C9 polymorphism and phenytoin toxicity Ataxia, nystagmus, drowsiness, gingival hyperplasia Genotype : CYP2C9*3/*3
  • 56. This girl may develop side effects to  Warfarin  Glibenclamide  Acenocoumarol  Tolbutamide  Losartan  Ibuprofen  Irbesartan  Flurbiprofen  Glipizde  Diclofenac All metabolized by CYP2C9 enzyme
  • 57. 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
  • 58. Pharmacogenomics Information in the Published Literature Zineh I et al. Ann Pharmacother. 2006; 40: 639-44
  • 60. Antidepressants  119 pharmacogenomic studies reported  CYP 2D6 , CYP 2C19  PM : more side effects  UM : more therapeutic effect  Association with 5 HTR2A , GRIK2 genes.
  • 61. Mood stabilizers  102 pharmacogenomic studies reported  Association with GRIA2, ODZ4 genes decrease efficacy
  • 62. Antipsychotics  84 pharmacogenomic studies reported  EPF1 ,NOVA 1 : antipsychotic induced parkinsonism  ZNF202 : extrapyramidal side effects
  • 63. Psychopharmacogenomics and Drug Development
  • 64. • 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).
  • 66. Genotyped Tacrine ApoE1 ApoE2 No statistical significant response ApoE3 ApoE4
  • 67. ApoE1 ApoE2 Stratify the patients according to genotypes ApoE4 ApoE3
  • 68. ApoE1 Tacrine No statistical ApoE2 significant response ApoE3
  • 69. Tacrine Statistical significant response ApoE4
  • 70. 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
  • 71. Phase I studies Exclude or include specific patients Normalize genotype frequencies
  • 72. 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
  • 73. 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)
  • 74. What are the anticipated benefits of Pharmacogenomics?
  • 75. Individualized Medicines Pharmaceutical companies will be able to create drugs based on the proteins, enzymes, and RNA molecules associated with genes and diseases. This will facilitate drug discovery and allow drug makers to produce a therapy more targeted to specific diseases. This accuracy not only will maximize therapeutic effects but also decrease damage to nearby healthy cells.
  • 76. 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)
  • 77. Some ethical Issues Could the development of medicines for specific groups of the population exclude others? Will the development of unprofitable, but desirable, medicines be neglected? Who will have access to genetic information and databases?
  • 78. 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
  • 79. Social Issues Health 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?
  • 80.
  • 81. Patient requires Treatment Examination by the Physician Genomic testing Traditional investigations EXPERT SYSTEM Decision making by Physician, assisted by an Expert System (interactive interpretation) Prescribes individualized drug treatment
  • 83.
  • 84.
  • 85. Roche AmpliChip: FDA-Approved CYP2D6 , CYP 2C19
  • 86. 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
  • 87. 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 mostly information related to drug metabolizing enzymes Around ~2050 it might include an entire individual genome (or at least, few millions SNPs..)
  • 88. Science or Science Fiction ? Unrealistic projections for 2025: Most medicines will be prescribed according to patient genotyping Genomics would allow full insight into the biological basis of complex human diseases
  • 89. PGx: Science and Science Fiction Realistic 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)
  • 92. 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
  • 93. 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 …
  • 94. Acknowledgements  Dr. Praveen Khairkar  Dr. Sushil Verma  Dr. Aniket Shukla  Dr. Adithan  Google and Wikipedia