Psychopharmacogenomics in Child & Adolescent Psychiatry Esmaeil Shahsavand Ananloo, MD, PhD Department of Genomic Psychiatry and Behavioral genomics (DGPBG) Roozbeh Hospital, School of Medicine Tehran University of Medical Sciences (TUMS) shahsavand@sina.tums.ac.ir 2nd. Congress of Pharmacotherapy in Child and Adolescent Psychiatrydolescent Psychiatry

CONTENTS I- Problem: Clinical Phenotype-Based Diagnosis II- A Few Solutions II-1) Phenomics-Based Diagnosis II-2) Endophenotype-Based Diagnosis II-3) Biomarker-Based Diagnosis III- Psychopharmacogenomics IV- Psychopharmacogenomics of ADHD; As an Example Summary

I- Problem: 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: Clinical Phenotype-Based Diagnosis Overlaps: ED OCD ADHD BD ASD Anxiety ...

I- Problem: Clinical Phenotype-Based Diagnosis Problem of Validity ! Problem of Reliability ! Problem of Diagnostic Stability ! Problem of Co-morbidity ! Problem of Treatment !

I- Problem: Clinical 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-1) Phenomics-based Diagnosis One-Level Approach (Clinical) Multi-Level Approach

II- A Few Solutions: II-1) Phenomics-based Diagnosis Phenome: Represents the sum total of the organism’s phenotypic traits: Transcriptome Proteomics Metabolomics ..... Change in response to genetic mutation and environmental influences. Phenomics: An area of biology concerned with the study and measurement of Phenomes.

II- A Few Solutions: II-1) Phenomics-based Diagnosis Research Team of the Future CNP Team 9

II- A Few Solutions: II-1) Phenomics-based Diagnosis 10

II- A Few Solutions: II-2) EndoPhenotype-based Diagnosis 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-2) EndoPhenotype-based Diagnosis

II- A Few Solutions: II-3) Biomarker-based Diagnosis Biomarkers (Biological markers) are defined as traits that are specific to particular conditions. Biomarkers (Better Diagnosis) Genomic Epigenomic Imaging Biochemical Anatomical ….. Identify clearly aetiopathological factors Carter et al, 2012; Stober et al, 2009

III- Pychopharmacogenetics The Best Drug Best Effect on Phenomics Levels Best Effect on Endophenotypes Best Effect on Biomarkers

Novel Discipline: Pychopharmacogenetics III- Pychopharmacogenetics Antipsychotics, antidepressants, anxiolytics and mood stabilising agents have all been discovered at the beginning of the 2nd. half of the 20th. century. 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. Novel Discipline: Pychopharmacogenetics

III- Pychopharmacogenetics Specifically relates to the genetic understanding of the variability in response to psychiatry drugs. 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.

maximal chance of positive response minimal risk of side effects III- Pychopharmacogenetics Drugs with: maximal chance of positive response minimal risk of side effects Giving: the right drug at the right dose to the right patient at the right time

CVD; DM; Cancer SCZ; BD; Autism 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.

ADHD; A few examples IV- Psychopharmacogenetics of ADHD; As an Example 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) Yanget al., 2004 DRD4 VNTR (48-bp variant) Cheon et al., 2007 DRD5 CA(n) microsatellite marker Thapar et al., 2007

ADHD; A few examples IV- Psychopharmacogenetics of ADHD; As an Example 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

I- Problem: Clinical Phenotype-Based Diagnosis II- A Few Solutions Summary I- Problem: Clinical Phenotype-Based Diagnosis II- A Few Solutions II-1) Phenomics-Based Diagnosis II-2) Endophenotype-Based Diagnosis II-3) Biomarker-Based Diagnosis III- Psychopharmacogenomics IV- Psychopharmacogenomics of ADHD; As an Example

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