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Slide 1: Pharmacogenetics - An Overview Jacob J. Venter, M.D Instructor: Harvard Medical School Medical Director Adolescent Assessment Unit Cambridge Health Alliance Boston, MA Adjunct Faculty: MIHS/MedPro Phoenix, AZ
Slide 2: Learning Objectives " " " " " " Definitions Overview of Clinical Applications Pharmacokinetic Aspects Pharmacodynamic Aspects Relevance to Understanding Pathogenesis Genetic Studies in Psychopharmacology Dopamine Serotonin " Future Directions
Slide 3: Definitions " Pharmacogenetics - study of genetic influences on drug response " Pharmacogenomics - using genetic information in drug design and treatment " Used interchangeably " Initial research dealt with catabolizing enzymes and how variations influence pharmacokinetics " More recently looking at pharmacodynamic aspects " How can genetic variation at site of action influence drug response?
Slide 4: Overview: Clinical Applications " Drug design More efficient and quicker due to better understanding of disease and target identification " Dose (and possibly) compound selection Better able to predict response Shorter exposure to medications Better monitoring of clinical response Less therapeutic trials Financial saving
Slide 5: Pharmacokinetic Aspects " Liver microsomal enzyme system " Brief review here " Phase I metabolism CYP 450 enzymes oxidize drugs  readily excreted forms Variation in this family of enzymes is related to polymorphisms in corresponding genes Varies across ethnic groups  differences in response to drugs Include CYP1A2, 2D6, 3A4, 3A5, 2C9, 2C19
Slide 6: Pharmacokinetic Aspects " Phase II metabolism Conjugative metabolic enzymes Relevant to all psychiatric drugs (except Lithium) Forms readily excreted conjugates with sulphate, acetyl and glucuronate moieties " Cumbersome application Assays extensive Genotyping of more pertinent polymorphisms will improve utility " Clinical applications
Slide 7: Pharmacodynamic Aspects " Focus of genetic variation at sites of drug action (limited number of studies) " Disorders studied include Alzheimer s disease Schizophrenia Depression Suicide Anxiety Disorders OCD Substance abuse (smoking, drugs, alcohol)
Slide 8: Pharmacodynamic Aspects " Focus on a few neuro-effector systems " Apolipoprotein and cholinergic system in Alzheimer s APOE-4 allele associated with " higher risk, altered lipid transport, " may influence drug response to anticholinesterase & cholinomimetics " DA & 5HT Involved in a large number of behavioral phenotypes, pharmacological agents and where a lot of work should be done " Very few studies on genes at play in the hypothalamic-pituitary-adrenal axis
Slide 9: Relevance to Understanding Pathogenesis " Drug development should be based on an understanding of pathophysiology " Response to treatment effects frequently used in psychiatry to generate theories of pathogenesis " Genome wide scanning can bring unexpected opportunities for novel targets
Slide 10: Relevance to Understanding Pathogenesis " Selecting candidate genes on basis of drug action has been done " Limited by a number of factors Heterogeneity of disease expression Incomplete understanding of drug actions Non-specificity and poly activity " Looking at drug effects on gene expression
Slide 11: Relevance to Understanding Pathogenesis " Genetic studies of pathogenesis without any preconceived notions may identify novel targets (genome-wide screens) " Animal models with knockout strategies may be helpful " Advances in combinatorial chemistry and structure-based drug design holds promise once targets are identified " Susceptibility genes lead to disease only when occurring in combination, environmental factors
Slide 12: Association Studies: DA-related alleles " Include DRD4, DRD5, DA  hydroxylase (DBH) and DAT studies " Replicated studies in ADHD " DAT with 10 copy repeat preferentially transmitted to offspring with ADHD (some, but not all) " Association also reported for DRD4 gene with higher frequency of the 7-, than 4-repeat allele (coding for a larger protein) " Found in both family-based association and casecontrol studies
Slide 13: DA-related alleles " Replicated studies in ADHD " Associations also reported for the DRD5 and DBH genes " DRD5 may be predictor for methyphenidate responders " May be specific relationships - DRD4 more associated with inattention and DAT with hyperactivity/impulsivity
Slide 14: DA-related alleles " Other disorders also studied with somewhat less robust findings " DAT and Bipolar Disorder " DRD4 and Tourette s Disorder (conflicting findings) " Novelty or sensation seeking related to 7copy allele of the DRD4 gene
Slide 15: Pharmacogenetics & DA " Few studies " Including drugs and alcohol increases # " Possible association between the TaqA1 allele of the D2 receptor (DRD2) and alcoholism " Other associations DRD2 - cocaine dependence DRD3 - drug dependence & schizophrenia DRD4 - nicotine dependence DRD5 - polysubstance dependence DAT - cocaine induced psychosis DBH - cocaine induced paranoia
Slide 16: Pharmacogenetics & DA " Genetic influences on treatment response - limited studies " Neuroleptic and clozapine response associated with DRD3 polymorphisms " DRD4 studies with clozapine suggests no correlation " Tardive dyskinesia may be related to DRD3 polymorphism, 1 study found relation with acute akathesia
Slide 17: Pharmacogenetics & DA " First study in child psychiatry in 1999 assessed the association between DRD2, DRD4 and DAT and methylphenidate response in ADHD " Lower response rate with 10-repeat allele of DAT " Included African-American boys only " Not replicated
Slide 18: Association studies: Serotonin-related alleles " 5HT2A, 5HT1B, serotonin transporter and tryptophan hydroxylase genes " Some looked at a functional polymorphism (5HTTLPR) in promoter region of the serotonin transporter gene " Serotonin transporter gene is a critical component of the 5HT system and principal site for the SSRIs " May also influence the action of other agents with 5HT action (atypicals, hallucinogens, precursors (tryptophan) and 5HT releasing agents (trazodone and fenfluramine)
Slide 19: Association studies: Serotonin-related alleles " Insertion/deletion polymorphism in promoter region seems functional " Insertion form (long or l) allele leads to higher levels of transporter gene expression and higher activity " Deletion form (short or s) allele results in lower mRNA levels, transporter protein expression and activity " Relation to clinical response not established
Slide 20: Association studies: Serotonin-related alleles " Disease association with s allele and neuroticism " OCD and the l allele " No association with Bipolar Disorder " Autism - associations with both reported " Reported association between less severely socially affected ASD and l allele
Slide 21: Association studies: Serotonin-related alleles " Other areas of interest " 5-HT2a receptor changes due to exposure to medications " 5-HT2c receptor - role in psychosis " Both these systems yielded contradictory and somewhat disappointing results this far
Slide 22: Pharmacogenetic Studies of the Serotonergic System " Interest in clozapine response and the effect on the 5-HT2A receptor " Diverse and large sample indicated relation between response at 6 months and 452Tyr allele " Very low predictive values, so screening not viable " Also possible relation between clozapine response and 5-HT2C polymorphism
Slide 23: Pharmacogenetic Studies of the Serotonergic System " Several uses of SSRIs " Difference in responses may be related to the HTT gene " Thoughts about the loss of efficacy of the SSRIs
Slide 24: Near Future Application " " " " P450 system genotyping Other SSRI related genes in association Boutique medicine Public health implications - safety, decreased exposure, rapid response, safety all factors that may be addressed