Dr. Swanand S Pathak

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

3. Part I
BASIC CONCEPTS

4. Genomics
 OM – COMPLETE
 GENE
 GENES
 GENOME
 ICS – STUDY
 GENOMICS

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.

9. NEED ?

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.

12. CONVENTIONAL DRUG DEVELOPMENT APPROACH

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

15. “Pharmacogenomics”

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.

17. HISTORY

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

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

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

28. Normal
Missense

29. Normal
Nonsense

30. Normal
Frameshift

31. Deleted area
Before After
deletion deletion

32. Duplicated area
Before
duplication
After
duplication

33. ? MOST
IMPORTANT

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

35. CYP 450

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

38. Chromosome 10q24.2
CYP2C9 CYP2C9
P M

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

45. Drug metabolism

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

49. Transport

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

51. Receptor sensitivity

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.

54. Adverse drug reaction

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

59. Antidepressants
Antipsychotics
Mood stabilizers

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).

65. Tacrine
No statistical significant response

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?

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

82. Tools for prediction

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)

90. “Hereis my
sequence”

91. TiPS 24:122-126 (2003)

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