I have NO actual or potential conflicts of interest in relation to this educational presentation.

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1 Genotyping The Patient Requiring Mental Health Medications: When Does It Make Sense? Charles F. Caley, PharmD, BCPP Clinical Professor UConn School of Pharmacy Storrs, CT I have NO actual or potential conflicts of interest in relation to this educational presentation. No Off-Label Discussions

2 Learning Objectives Discuss genomic variability in terms of psychotropic drug outcomes; Describe clinical pharmacogenomic tests that practitioners can use in support of clinical care; Understand the limitations of clinical pharmacogenomic testing as applied to the use of psychotropic medications. Self Assessment Genetic variability can result in differences in drug metabolism, drug distribution and drug action. Genotyping CYP2D6, 2C19 and 2C9 can help us identify which patients will be a responder to psychotropic medications. For patients with ADHD, genotyping a patient s serotonin transporter gene can help us identify who will respond to methylphenidate. Self Assessment For patients with depression, genotyping a patient s alpha-2a receptor gene can help us identify who will respond to an SSRI. A patient with a history of poor tolerability to several medications that are each metabolized by the same enzyme may be a reason to genotype that enzyme. The time has come for us to be genotyping most, if not all, our patients.

3 Psychotropic Drug Outcome Variability Treatment Response Tolerability Dose Effect Relationship in Pharmacology Drug dose Biologic fluid concentration Effect site concentration Pharmacologic effect Pharmacokinetic variability Bioavailability (F) Metabolism Protein binding/protein status Sub optimal adherence Efflux transport Pharmacodynamic variability Target site [ ] Affinity Dissociation Other drugs

4 accessed on 15 May accessed on 22 May 2013

5 accessed on 22 May 2013 Pgp export pump [ target site Metabolism Distribution Absorption Elimination Drug Metabolism CYP450* Drug Metabolite #1 Metabolite #1 UDPG* Metabolite #2 *Activity modifiable by other meds, and by genetics

6 CYP450 Genes CYP450 ENZYME CHROMOSOME ALLELES* 1A B C C D E A *Reported/proposed from accessed on 15 May 2013 CYP2D6 Allele Frequency Bradford LD. Pharmacogenomics 2002;3(2): Metabolizer Status (Phenotype) CYP 450 enzymes - Extensive metabolizers (EM) Metabolizer status for most Two copies of wild type allele e.g.,*1a / *1A - Ultra-rapid metabolizers (UM) Effects 2D6 and 1A2 Mutiple gene copies of a functional allele e.g., *1AX2 / *1A Black JL, et al. Expert Opin Drug Metab Toxicol 2007;3:21 31.

7 Metabolizer Status (Phenotype) CYP 450 enzymes - Intermediate metabolizers (IM) In between EM and poor metabolizer Combination of one wild type allele and one allele coding for either partially or completely deficient enzyme activity e.g., *1A / *3 - Poor metabolizers (PM) Combination of alleles where each codes for either partially or completely deficient enzyme activity Black JL, et al. Expert Opin Drug Metab Toxicol 2007;3: Drug Action Serotonin Transporter Alleles Canli T, Lesch KP. Nature Neuroscience 2007;10(9):

8 Murdoch JD, et al. Biol Psychiatry 16 March 2013; doi = P-Glycoprotein O Brien FE, et al. Br J Pharmacol 2012;165: P-Glycoprotein O Brien FE, et al. Br J Pharmacol 2012;165:

9 Lin KM, et al. Pharmacogenet Genomics 2011;21: Evans WE, Relling MV. Science 1999;286: Treatment Outcomes Dependent upon: - Proper dx, proper tx selected - Environmental stress - Dose/duration of tx - Genetics Pharmacokinetics Pharmacodynamics - Other medications - Patient adherence to tx

10 Clinical PGx Tests Psychotropics w/ PGx Labeling Biomarker Therapeutic Area Medications CYP2C19 Depression/Anxiety Citalopram, diazepam CYP2D6 ADHD Depression/Anxiety Miscellaneous Atomoxetine Aripiprazole, citalopram, clomipramine, desipramine, doxepin, fluoxetine, fluvoxamine, nefazodone, nortriptyline, paroxetine, venlafaxine Codeine, fluoxetine/olanzapine, iloperidone, modafinil, perphenazine, risperidone HLA-B*1502 Bipolar disorder Carbamazepine UCD Bipolar disorder Valproic acid accessed on 15 May 2013 Straterra accessed on 23 May 2013

11 Celexa accessed on 23 May 2013 Poor Metabolizer Increased risk of achieving excessive concentrations of drug with conventional dosing increased risk of poor tolerability d/t adverse effects Adverse Drug Concentration Using Conventional Dosing Therapeutic Ineffective Time CF Caley, Pharm.D., BCPP Ultra-Rapid Metabolizer Increased risk of not achieving adequate concentrations of drug with conventional dosing increased risk of poor therapeutic response Adverse Drug Concentration Using Conventional Dosing Therapeutic Ineffective Time CF Caley, Pharm.D., BCPP

12 Codeine Crews KR, et al. Clin Pharmacol Ther 2012;91(2): Crews KR, et al. Clin Pharmacol Ther 2012;91(2): Lab Web Location PGXL Laboratories pgxlab.com Louisville, KY Millenium Laboratories milleniumlabs.com San Diego, CA Genelex youscript.com Seattle, WA Genesys Diagnostics gdilabs.com East Lyme, CT ARUP Laboratories aruplabs.com Salt Lake City, UT Genomas genomas.net Hartford, CT Genova Diagnostics gdx.net Duluth, GA Genomind genomind.com Chalfont, PA Mayo Medical Labs mayomedicallaboratories.com Rochester, MN AssureRx assurerxhealth.com Mason, OH

13 Laboratory of Personalized Health LABORATORY OF PERSONALIZED HEALTH CT License: CL-0644 CLIA: # 07D LPH Genomas Inc. 67 Jefferson Street Hartford, CT Tel: (860) Fax: (860) HILOmet 2D6 CYTOCHROME P450 DNA TYPING REPORT, GENE CYP2D6 Patient Name: Patient ID: LPH ID: Patient Date of Birth: Date of specimen receipt into laboratory: Name of Physician/Authorized person requesting test: ALLELES. CARRIER STATUS METABOLIZER STATUS WT *5 Gene Duplication Ultra-rapid *17 *6 Normal Functional *4 *3 Carrier Deficient *9 *10 Double Null Duplication Other: Specimen did not meet LPH acceptability Comments/recommendations : Please refer to the LPH website at for additional clinical and scientific background information. Test Report Date Signed: Gualberto Ruaño, M.D., Ph.D. Laboratory Director 1. The HILOmet System should be used only in conjunction with clinical presentation and other diagnostic data when making therapy decisions. A Patient s response to drug therapy depends on multiple non-genetic factors, including patient compliance with drug regimen, interactions with other medications, and diet. 2. The HILOmet System, including DNA extraction and DNA typing of cytochrome p450 genes, was performed by the Laboratory of Personalized Health (LPH) under its license from the CT Department of Public Health (license CL-0644) and certification with the Centers for Medicare and Medicaid (ID# 07D ) under the CLIA (Clinical Laboratory Improvement Amendments). The HILOmet test has not been cleared or approved by the U.S. Food and Drug Administration (FDA): FDA approval or clearance is not required for the HILOmet System. accessed on 15 May 2013 GeneSightRx ADHD Results Patient, Sample DOB: 11/14/1984 Reference: Order N Clinician: Report Date: 4/23/2012 USE AS DIRECTED USE WITH CAUTION USE WITH INCREASED CAUTION AND WITH MORE FREQUENT MONITORING dexmethylphenidate (Focalin ) [4] methylphenidate (Ritalin, Concerta, Metadate, Daytrana ) [4] atomoxetine (Strattera ) [5] amphetamine salts (Adderall ) [1] dextroamphetamine (Dexedrine ) [1] lisdexamfetamine (Vyvanse ) [1] [1]: CYP2D6 genotype indicates that blood levels may be increased for this drug. [2]: CYP2D6 genotype indicates that blood levels may be decreased for this drug. [3]: COMT genotype is associated with reduced therapeutic response to this drug. [4]: ADRA2A genotype is associated with improved response to this drug. [5]: CYP2D6 genotype indicates that this patient may experience increased side-effects, but also increased efficacy All ADHD medications require clinical monitoring. Drugs are reported in alphabetical order. This report is not intended to imply that the drugs listed are approved for the same indications or that they are comparable in safety or efficacy. The brand name is shown for illustrative purposes only; other brand names may be available. The prescribing physician should review the prescribing information for the drug(s) being considered and make treatment decisions based on the patient's individual needs and the characteristics of the drug prescribed. Patient Genotypes and Phenotypes CYP2D6 Poor Metabolizer *4/*4 CYP2D6*4: This allele produces no enzyme activity. CYP2D6*4: This allele produces no enzyme activity. Comment: This genotype is associated with a poor metabolizer phenotype. This patient may have reduced enzyme activity as compared to individuals with the normal genotype. COMT High Activity VAL/VAL This patient does not carry the Met allele and may be expected to experience a positive response with stimulants. ADRA2A Improved Response C/G This patient is heterozygous for the G allele and is more likely to experience an improved response to methylphenidate and dexmethylphenidate. Order: 2 Report Date: 4/23/2012 CONFIDENTIAL HEALTHCARE INFORMATION 2012 AssureRx Health, Inc. All Rights Reserved Patient, Sample Page 1 of 3

14 PGx Testing Many options available - Drug metabolizing tests most widely used - Some drug target test available - Actively being marketed - Generally not covered by health insurance PGx testing best used in situations where accumulating clincal outcome evidence points to consistent non-response or non-tolerability... - But only in specific conditions Limitations Drug Metabolism CYP450* Drug Metabolite #1 Metabolite #1 UDPG* Metabolite #2 *Activity modifiable by other meds, and by genetics

15 Citalopram Metabolism Baumann P, et al. Euro Neuropsychopharm 2002;12(5): Diazepam Metabolism Inomata S, et al. Clin Pharmacol Ther 2005;78: MDD Wagner G, et al. J Psychiatry Neurosci 2008;33(3):

16 ADHD Cognitive Attention Network (Cingulo-Frontal Parietal) Liston C, et al. Biol Psychiatry 2011;69: Good Poor (Val/Val vs Val/Met vs Met/Met; p =.035) 80 % Val/Val Val/Met Met/Met 11.7 Cheon KA et al. Int Clin Psychopharmacology 2008;23: Good Poor (Val/Val vs Val/Met vs Met/Met; p =.034) 80 % Val/Val Val/Met Met/Met Cheon KA et al. Int Clin Psychopharmacology 2008;23:291-8.

17 Limitations Tendancy to simplify drug metabolism Incomplete understanding of pathophysiology Inconsistent results for replicating genetic association between biomarkers and outcomes - Patient sample diagnostic heterogeneity - Study methodologies Screening for specific polymorphisms vs. performing genome-wide association Key variables: treatment non-adherence; impact of environmental stress; impact of other genes Pharmacogenomics: Challenges and Opportunities in Therapeutic Implementation. Academic Press, Waltham, MA. Lam YF, Cavallari LH, eds. So, Who Should Be Genotyped?

18 Poor Tx Outcome Document: - Drug-pharmacokinetics-pharmacodynamics - Tx adherence - Specific outcomes Poor symtpomatic improvement Poor tolerability - Other medications How many failed treatment trials are needed before we genotype? Scenario A 21 yo caucasian male student with ADHD is treated with atomoxetine and instructed to start 40 mg/day for 3 days and then increase to 80 mg/day which they are to take until their next clinic appointment. By the end of the third day of atomoxetine 40 mg/day, the student calls complaining of tachycardia (HR = 120 bpm), elevated blood pressure (130/90), extreme nausea and insomnia. No other meds, otherwise healthy. - What might we predict this patient s metabolizer status to be based on this brief clinical scenario? - How might this scenario be interpreted if there was no genotype data?...if the patient were known to be a 2D6EM? Scenario A 20 yo AA female student with MDD presents to health services in an episode of major depression. The student has failed three antidepressant treatment trials: fluoxetine 40 mg/day x 8 weeks, paroxetine 40 mg/day x 8 weeks and venlafaxine 300 mg/day x 10 weeks. The patient reports that for each antidepressant treatment trial she took the medication as intended and that despite this, she received no therapeutic benefit. She states It was like I didn t even have any side effects! - What might we predict this patient s metabolizer status to be? - What might we predict this patient s 5HT transporter genotype to be? - How might this scenario be interpreted if there was no genotype data?...if the patient were known to be a 2D6EM?

19 Tan-kam T, et al. Pharmacogenomics and Personalized Medicine 2013:6:3 7. Summary