psychopharmacogenomics in child & adolescent psychiatry esmaeil shahsavand ananloo, md, phd...
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Psychopharmacogenomics Psychopharmacogenomics
in in
Child & Adolescent PsychiatryChild & Adolescent Psychiatry
Esmaeil Shahsavand Ananloo, MD, PhDEsmaeil Shahsavand Ananloo, MD, PhDDepartment of Genomic Psychiatry and Behavioral genomics (DGPBG)Department of Genomic Psychiatry and Behavioral genomics (DGPBG)
Roozbeh Hospital, School of MedicineRoozbeh Hospital, School of Medicine
Tehran University of Medical Sciences (TUMS)Tehran University of Medical Sciences (TUMS)
2nd. Congress of Pharmacotherapy in Child and Adolescent Psychiatrydolescent Psychiatry2nd. Congress of Pharmacotherapy in Child and Adolescent Psychiatrydolescent Psychiatry
CONTENTS
I- Problem: Clinical Phenotype-Based DiagnosisI- Problem: Clinical Phenotype-Based Diagnosis
II- A Few Solutions II- A Few Solutions
II-1) Phenomics-Based DiagnosisII-1) Phenomics-Based Diagnosis
II-2) Endophenotype-Based DiagnosisII-2) Endophenotype-Based Diagnosis
II-3) Biomarker-Based DiagnosisII-3) Biomarker-Based Diagnosis
III- PsychopharmacogenomicsIII- Psychopharmacogenomics
IV- Psychopharmacogenomics of ADHD; As an ExampleIV- Psychopharmacogenomics of ADHD; As an Example
SummarySummary
I- Problem:I- Problem: Clinical Phenotype-Based Diagnosis Clinical Phenotype-Based Diagnosis
Current treatment strategies rely:
✴ Rely on symptom-based diagnosis (DSM and ICD)
✴ Based on symptom clusters rather than the underlying
EtioPathophysiology
Clinical Phenotype: A Serious Problem
Because: No Pathognomonic Symptom !
I- Problem:I- Problem: Clinical Phenotype-Based DiagnosisClinical Phenotype-Based Diagnosis
Overlaps:Overlaps:
•EDED
•OCDOCD
•ADHDADHD
•BDBD
•ASDASD
•AnxietyAnxiety
•......
I- Problem:I- Problem: Clinical Phenotype-Based DiagnosisClinical Phenotype-Based Diagnosis
✴ Problem of Validity !
✴ Problem of Reliability !
✴ Problem of Diagnostic Stability !
✴ Problem of Co-morbidity !✴Problem of T
reatment !
I- Problem:I- Problem: Clinical Phenotype-Based DiagnosisClinical Phenotype-Based Diagnosis
Drugs: absence of predictive factors for efficacy.
Physicians:
Rely on their own experience
With a considerable element of trial and error prescribing
II- A Few Solutions:II- A Few Solutions: II-1) II-1) Phenomics-based DiagnosisPhenomics-based Diagnosis
Mu
lti-
Lev
el A
pp
roac
h One-Level Approach
(Clinical)
II- A Few Solutions:II- A Few Solutions: II-1) II-1) Phenomics-based DiagnosisPhenomics-based Diagnosis
✴Phenome:
✴Represents the sum total of the organism’s phenotypic traits:
✴Transcriptome
✴Proteomics
✴Metabolomics
✴.....
✴Phenomics:
✴ An area of biology concerned with the study and
measurement of Phenomes.
Change in response to genetic mutation and environmental influences.
9
II- A Few Solutions:II- A Few Solutions: II-1) II-1) Phenomics-based DiagnosisPhenomics-based Diagnosis
Research Team of the FutureResearch Team of the Future
CNP TeamCNP Team
10
II- A Few Solutions:II- A Few Solutions: II-1) II-1) Phenomics-based DiagnosisPhenomics-based Diagnosis
II- A Few Solutions:II- A Few Solutions: II-2) II-2) EndoPhenotype-based DiagnosisEndoPhenotype-based Diagnosis
Endophenotype:
✦ Is a Genetic Epidemiology term
✦ Is more stable Phenotype
✦ With a clear Genetic connection
In Psychiatric Genetics:
✦ To bridge the gap between high-level symptom presentation &
✦ low-level genetic variability, such as: SNPs, CNVs
II- A Few Solutions:II- A Few Solutions: II-2) II-2) EndoPhenotype-based DiagnosisEndoPhenotype-based Diagnosis
II- A Few Solutions:II- A Few Solutions: II-3) II-3) Biomarker-based DiagnosisBiomarker-based Diagnosis
Identify clearly aetiopathological factorsCarter et al, 2012; Stober et al, 2009
Biomarkers (Biological markers) are
defined as traits that are specific to
particular conditions.
Biomarkers (Better Diagnosis) Genomic Epigenomic Imaging Biochemical Anatomical …..
III- Pychopharmacogenetics
The Best Drug
Best Effect on Phenomics Levels
Best Effect on Endophenotypes
Best Effect on Biomarkers
Antipsychotics, antidepressants, anxiolytics and mood stabilising agents have
all been discovered at the beginning of the 2nd. half of the 20th. century.
Novel Discipline: Pychopharmacogenetics
III- Pychopharmacogenetics
However, serious limitations are:
Relatively low response rate
Unpredictibility of the response
Deleterious side effects (quality of life / poor compliance)
A new step in the development of better treatments
Improving the design and synthesis drug molecules
Considering the genotype as a possible reason for good, poor or
no responding to drugs.
Specifically relates to the genetic understanding of the variability in
response to psychiatry drugs.
III- Pychopharmacogenetics
Use of genetic markers as part of a physician’s decision-making criteria.
Reduces the reliance on trial and error prescribing.
Ultimately lead to more effective medicines and improved healthcare for
patients.
Drugs with:
maximal chance of positive response
minimal risk of side effects
III- Pychopharmacogenetics
Giving:
the right drug
at the right dose
to the right patient
at the right time
III- Pychopharmacogenetics
deCODE genetics, Inc. ✤Is a biopharmaceutical company based in Iceland.
✤Was founded in 1996.
✤To identify human genes associated with common diseases using population studies.
✤Apply the knowledge gained to guide the development of candidate drugs.
CVD; DM; Cancer
SCZ; BD; Autism
IV- Psychopharmacogenetics of ADHD; As an ExampleIV- Psychopharmacogenetics of ADHD; As an Example
ADHD; A few examples
Gene (Chr.) Marker Drug Response Reference
MAO-A (Chr. X) VNTR (4-repeat allele of MAOA 30 bp)
Response to methylphenidate
Grevet et al., 2007
NET G1287A(A/A genotype)
Response to methylphenidate
Yanget al., 2004
DRD4 VNTR (48-bp variant)
Response to methylphenidate
Cheon et al., 2007
DRD5 CA(n) microsatellite marker
Response to methylphenidate
Thapar et al., 2007
IV- Psychopharmacogenetics of ADHD; As an ExampleIV- Psychopharmacogenetics of ADHD; As an Example
ADHD; A few examples
Gene (Chr.) Marker Drug Response Reference
DAT1 VNTR (9-repeat allele in 3’UTR)
Non-Response to methylphenidate
Stein et al., 2002
VNTR (10-repeat allele in 3’UTR)
Response to methylphenidate
Kirleyet al. (2003
Summary
I- Problem: Clinical Phenotype-Based DiagnosisI- Problem: Clinical Phenotype-Based Diagnosis
II- A Few Solutions II- A Few Solutions
II-1) Phenomics-Based DiagnosisII-1) Phenomics-Based Diagnosis
II-2) Endophenotype-Based DiagnosisII-2) Endophenotype-Based Diagnosis
II-3) Biomarker-Based DiagnosisII-3) Biomarker-Based Diagnosis
III- PsychopharmacogenomicsIII- Psychopharmacogenomics
IV- Psychopharmacogenomics of ADHD; As an ExampleIV- Psychopharmacogenomics of ADHD; As an Example
Thanks IndeedThanks Indeed
