PsychoPsychopharmacopharmacogenomgenomicsics

conceptual reality or awaiting conceptual reality or awaiting dream? dream?

Dr. Swanand S PathakDr. Swanand S Pathak

MBBS MD DACM IDCR MBBS MD DACM IDCR

Dept. of PharmacologyDept. of Pharmacology

JNMC, SawangiJNMC, Sawangi

drswanandp@yahoo.co.indrswanandp@yahoo.co.in

Part I Part I ( basic concepts )( basic concepts )

What is pharmacogenomics What is pharmacogenomics Difference between the pharmacogenetics and Difference between the pharmacogenetics and

pharmacogenomics.pharmacogenomics. What is psychopharmacogenomics What is psychopharmacogenomics Historical aspects of pharmacogenomics Historical aspects of pharmacogenomics What are SNPsWhat are SNPs Concept of CYP enzymes and geneticsConcept of CYP enzymes and genetics

Part II Part II ( neuropsychopharmacogenomics)( neuropsychopharmacogenomics)

Psychopharmacogenomics in relation to antideparessants , Psychopharmacogenomics in relation to antideparessants , atipsyachotics and mood stabilizersatipsyachotics and mood stabilizers. .

Psychopharmacogenomics in relation with the drug development Psychopharmacogenomics in relation with the drug development in psychiatry in psychiatry

Part I Part I

BASIC CONCEPTSBASIC CONCEPTS

GenomicsGenomics OM – COMPLETE OM – COMPLETE

GENEGENE

GENES GENES

GENOMEGENOME

ICS – STUDYICS – STUDY

GENOMICSGENOMICS

PharmacoPharmacogenomics genomics

Drugs + genome = health benefit Drugs + genome = health benefit

PharmacogeneticsPharmacogenetics : study of the : study of the effect of effect of single gene single gene on the response on the response of various drugs of various drugs

Pharmacogenomics Pharmacogenomics : study of the : study of the effect of effect of multiple genes multiple genes on the on the response of various drugs response of various drugs

PsychoPsychopharmacogenomicspharmacogenomics ::

Study of the effects of variations in Study of the effects of variations in multiple genes on the response of multiple genes on the response of drugs used in psychiatrydrugs used in psychiatry and the and the psychiatric disorders.psychiatric disorders.

NEED ?NEED ?

Variability in Drug ResponseVariability in Drug Response

DiseaseDisease Drug ClassDrug Class Rate of Poor Rate of Poor responseresponse

AsthmaAsthma Beta-agonistsBeta-agonists 40-75%40-75%HypertensionHypertension VariousVarious 30%30%Solid CancersSolid Cancers VariousVarious 70%70%DepressionDepression SSRIs, tricyclicsSSRIs, tricyclics 20-40%20-40%DiabetesDiabetes Sulfonylureas, othersSulfonylureas, others 50%50%ArthritisArthritis NSAIDs, COX-2 inhibitorsNSAIDs, COX-2 inhibitors 30-60%30-60%SchizophreniaSchizophreniaVariousVarious 25-75%25-75%

( lieberman et al N Engl J Med 2005)( lieberman et al N Engl J Med 2005)

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

74% discontinued : lack of efficacy or 74% discontinued : lack of efficacy or tolerability.tolerability.

CONVENTIONAL DRUG DEVELOPMENT APPROACH

Scenario Scenario

All patients with same diagnosis

1

2Responders and patients not predisposed to toxicity

Non-respondersand toxic

responders

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

““PharmacogenomicsPharmacogenomics” ”

Pharmacogenomics holds the promise that drugs might one Pharmacogenomics holds the promise that drugs might one

day beday be tailor-madetailor-made for individuals and adapted to for individuals and adapted to each person's own genetic makeup.each person's own genetic makeup.

Environment, diet, age, lifestyle, and state of health Environment, diet, age, lifestyle, and state of health all can all can influence a person's response to medicines, but influence a person's response to medicines, but

understanding an individual's genetic makeup is thought understanding an individual's genetic makeup is thought to be the key to creating personalized drugs with greater to be the key to creating personalized drugs with greater

efficacy and safety.efficacy and safety.

HISTORY HISTORY

Important FactsImportant Facts Human genome = 22 chromosome pairs Human genome = 22 chromosome pairs

and 1 pair of sex chromosomesand 1 pair of sex chromosomes

Functional unit of the genome = geneFunctional unit of the genome = gene

2% of genes code for proteins, remainder 2% of genes code for proteins, remainder is structural for DNAis structural for DNA

Entire genome = 3 billion DNA pairs, with Entire genome = 3 billion DNA pairs, with ~30,000 protein coding genes~30,000 protein coding genes

AlleleAllele

An allele is one member of a pair that An allele is one member of a pair that makes up a genemakes up a gene

2 same alleles are 2 same alleles are homozygoushomozygous (one allele (one allele on each part a pair of chromosomes)on each part a pair of chromosomes)

2 different alleles are 2 different alleles are heterozygousheterozygous

• 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

After Before deletion deletion

Duplicated area

Before duplication

After duplication

?? MOST MOST IMPORTANTIMPORTANT

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 450CYP 450

Cytochrome P450 enzyme system Cytochrome P450 enzyme system terminologyterminology

Cytochrome P450 enzyme system Cytochrome P450 enzyme system terminologyterminology

““CYP”CYP” - P450 for all mammalian - P450 for all mammalian speciesspecies

““2”2” - family (17 - 14 human)- family (17 - 14 human) ““C”C” - subfamily (42 in humans)- subfamily (42 in humans) ““9”9” - enzyme/gene (55 genes)- enzyme/gene (55 genes) *2: *2: -Allele pattern-Allele pattern

CYP2C9 *2

23 SETS OF HUMAN CHROMOSOMES

Chromosome 10q24.2

CYP2C9 CYP2C9

P M

Impact of CYP2C9*2 genetic polymorphism on enzymatic activity

C G T Nucleotide # 430

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?What do the CYPs do?

Drug metabolism throughout Drug metabolism throughout the bodythe body

Activate drugsActivate drugs Detoxify substances and Detoxify substances and

activate non-toxic substances activate non-toxic substances into toxic substancesinto toxic substances

Proportion of Drugs Metabolized by CYP Enzymes

Proportion of Drugs Metabolized by CYP Enzymes

CYP3A4/536%

CYP2C8/916%

CYP1A1/211%

CYP2E14%

CYP2A63%

CYP2B63%

CYP2C198%

CYP2D619%

Neuro Neuro psychopharmacogenompsychopharmacogenom

ics ics

Part IIPart II

Consequences of polymorphisms

Drug metabolism Drug transport

Disease Receptor Polymorphisms susceptibility sensitivity

ADR

Disease susceptibility Disease susceptibility

Alzheimer’s disease : Apo E Alzheimer’s disease : Apo E

Drug metabolism 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

caucasiansFM

CYP2C19 *1/*1 20 hours

AsiansPM

CYP2C19 *2/*2 84 hours

Transport 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

Receptor Sensitivity/Effect

Subjects with Gly 389 have reduced β1 receptor gene

sensitivity to beta-blockers

Arg389Gly

Ser49Gly Subjects with Gly 49 have increased sensitivity to beta-blockers

Podlowski, et al. J Mol Med 2000;78:90.

Beta-1 Adrenergic ReceptorBeta-1 Adrenergic Receptor

Codon 49 SerGly

Codon 389ArgGly

Adverse drug reaction 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 CYP2D6 Polymorphisms and Psychiatric Drug ResponsePsychiatric Drug Response

Increased rate of adverse effects in poor Increased rate of adverse effects in poor metabolizers due to increased plasma metabolizers due to increased plasma concentrations of drug:concentrations of drug:

Fluoxetine Fluoxetine (Prozac(Prozac) death in child attributed to ) death in child attributed to CYP2D6 poor metabolizer genotypeCYP2D6 poor metabolizer genotype

Side effects of antipsychotic drugs occur more Side effects of antipsychotic drugs occur more frequently in CYP2D6 poor metabolizersfrequently in CYP2D6 poor metabolizers

CYP2D6 poor metabolizers with severe mental CYP2D6 poor metabolizers with severe mental illness had more adverse drug reactions, illness had more adverse drug reactions, increased cost of care, and longer hospital staysincreased cost of care, and longer hospital stays

Pharmacogenomics Information in Pharmacogenomics Information in the Published Literaturethe Published Literature

Zineh I et al. Ann Pharmacother. 2006; 40: 639-44

Antidepressants Antidepressants

Antipsychotics Antipsychotics

Mood stabilizers Mood stabilizers

AntidepressantsAntidepressants 119 pharmacogenomic studies reported 119 pharmacogenomic studies reported

CYP 2D6 , CYP 2C19CYP 2D6 , CYP 2C19

PM : more side effects PM : more side effects

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

Mood stabilizers Mood stabilizers

102 pharmacogenomic studies 102 pharmacogenomic studies reported reported

Association with GRIA2, ODZ4 genes Association with GRIA2, ODZ4 genes decrease efficacy decrease efficacy

AntipsychoticsAntipsychotics

84 pharmacogenomic studies reported 84 pharmacogenomic studies reported

EPF1 ,NOVA 1 : antipsychotic induced EPF1 ,NOVA 1 : antipsychotic induced parkinsonism parkinsonism

ZNF202 : extrapyramidal side effects ZNF202 : extrapyramidal side effects

PsychopharmacogenomicPsychopharmacogenomics s

and and

Drug DevelopmentDrug 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

ApoE2 ApoE1

Stratify the patients according to genotypes

ApoE4 ApoE3

ApoE1

Tacrine No statistical

significant response ApoE2

ApoE3

Tacrine Statistical significant response

ApoE4

Pre-clinical Gene ExpressionPre-clinical Gene Expression

Toxicogenomics Toxicogenomics

Predict toxicity of candidate compoundsPredict toxicity of candidate compounds Identify mechanisms of toxicityIdentify mechanisms of toxicity

Identify potential biomarkers for Identify potential biomarkers for toxicity or efficacy for future clinical toxicity or efficacy for future clinical studiesstudies

Phase I studies

Exclude or include specific patients

Normalize genotype frequencies

Phase II/III studiesPhase II/III studies

Identify genetically-defined groups Identify genetically-defined groups with more pronounced or rapidly with more pronounced or rapidly progressing diseaseprogressing disease

Exclude/include at-risk individualsExclude/include at-risk individuals Stratify studies based on Stratify studies based on

genotypesgenotypes Clinical responseClinical response Risk of adverse eventsRisk of adverse events

Where appropriate, develop drugs Where appropriate, develop drugs for specific groupsfor specific groups

FDA and PharmacogenomicsFDA and Pharmacogenomics FDA published: “Draft Guidance for FDA published: “Draft Guidance for

Industry: Pharmacogenomic Data Industry: Pharmacogenomic Data Submission” in 2003. (currently under Submission” in 2003. (currently under revision)revision)

Set criteria for Voluntary Genomic Data Set criteria for Voluntary Genomic Data Submission (VGDS)Submission (VGDS)

(http://www.fda.gov/cder/guidance/5900dft.pdf)

What are the anticipated What are the anticipated benefits of benefits of

Pharmacogenomics?Pharmacogenomics?

Individualized MedicinesIndividualized Medicines

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

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

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

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

Who will have access to genetic information Who will have access to genetic information and databases?and databases?

Research IssuesResearch Issues

• 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

Translating

Social IssuesSocial Issues Will I develop this Will I develop this

disease ten years disease ten years from now?from now?

• • Can I indulge in Can I indulge in unhealthy habits unhealthy habits (e.g., smoking, junk(e.g., smoking, junk

food, not food, not exercising, etc.) if I exercising, etc.) if I don’t have a don’t have a particular disease particular disease susceptibility?susceptibility?

Health Horoscope

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 Tools for prediction

Roche AmpliChip: FDA-ApprovedRoche AmpliChip: FDA-ApprovedCYP2D6 , CYP 2C19CYP2D6 , CYP 2C19

The Next Diagnostic Chips?The Next Diagnostic Chips?

Additional diagnostics are neededAdditional diagnostics are needed::

GeneralGeneral: CYP2C9; CYP3A5; CYP2B6; : CYP2C9; CYP3A5; CYP2B6; MDR-1; UDP Glucuronosyltransferases MDR-1; UDP Glucuronosyltransferases (UGTs); (UGTs); N-acetyltransferases (NATs)N-acetyltransferases (NATs)

OncologyOncology: : thiopurine thiopurine methyltransferase (methyltransferase (TMPT); TMPT);

Thymidilate synthase; Thymidilate synthase; dihydropyrimidine dehydrogenase dihydropyrimidine dehydrogenase (for 5-FU dosing)(for 5-FU dosing)

S M A R T C A R D

Praveen khairkar97236407611

GENOME(Confidential)

Personalized Medicine: “when?”

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..)

In your wallet by 2025?

Or maybe by 2050?

Science or Science Fiction ?Science or Science Fiction ?

Unrealistic projections for 2025:Unrealistic projections for 2025:

MostMost medicines will be prescribed medicines will be prescribed according to patient genotypingaccording to patient genotyping

Genomics would allow Genomics would allow full insightfull insight into the biological basis of complex into the biological basis of complex human diseaseshuman diseases

PGx: Science and Science FictionPGx: Science and Science Fiction

Realistic projections for 2025Realistic projections for 2025Genotyping would allow far smaller Genotyping would allow far smaller rates of adverse reactions for most rates of adverse reactions for most drugsdrugs

In several medical disciplines, In several medical disciplines, genomics would allow far better genomics would allow far better medical treatment medical treatment

(oncology; psychiatry; neurology) (oncology; psychiatry; neurology)

“Here is my sequence”

TiPS 24:122-126 (2003)

Part IPart I

What is pharmacogenomics What is pharmacogenomics Difference between the pharmacogenetics and Difference between the pharmacogenetics and

pharmacogenomics.pharmacogenomics. What is psychopharmacogenomics What is psychopharmacogenomics Historical aspects of pharmacogenomics Historical aspects of pharmacogenomics What are SNPsWhat are SNPs Concept of CYP enzymes and geneticsConcept of CYP enzymes and genetics

Part IIPart II

Psychopharmacogenomics in relation to antideparessants , Psychopharmacogenomics in relation to antideparessants , atipsyachotics and mood stabilizersatipsyachotics and mood stabilizers. .

Psycchopharmacogenomics in relation with the drug Psycchopharmacogenomics in relation with the drug development in psychiatry development in psychiatry

Conceptual reality or awaiting dream ?Conceptual reality or awaiting dream ?

Definitely a Definitely a conceptualconceptual reality reality

For grass root patients and For grass root patients and practitioners … there is still a long practitioners … there is still a long long way to go …to fulfill the dream long way to go …to fulfill the dream … …

AcknowledgementsAcknowledgements

Dr. Praveen Khairkar Dr. Praveen Khairkar Dr. Sushil VermaDr. Sushil Verma Dr. Aniket Shukla Dr. Aniket Shukla Dr. Adithan Dr. Adithan Google and Wikipedia Google and Wikipedia