Jay Lombard, DO October 28, 2011

Personalized Medicine And The Science Behind

The GeneceptTM Assay

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!  Genomind Chief Scientific Officer and Chief Medical Officer

!  Nationally recognized leader in neuropsychiatry practice, research and thought leadership.

!  Former Chief of Neurology and head of the Stroke Department at Bronx Lebanon Hospital

!  Clinical Instructor of Neurology at Albert Einstein College of Medicine and the Assistant Clinical Professor of Neurology at Weill Cornell Medical College of Cornell University

!  Author of critically acclaimed books, including Freedom from Disease, Balance Your Brain, and The Brain Wellness Plan.

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!  Treatment efficacy is often unsatisfactory with high rates of side effects and incomplete remission in many patients, leading to trial and error approach

!  Diagnosis of many patients is often complex and confusing

!  Psychiatric disorders are often dimensional, not categorical with overlapping phenotypes

!  Patients and families often ask about the availability of tests to assist in management

!  Biomarkers reduce stigma of psychiatric disorders - with bio underpinnings, disorders are medical

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!  The assay analyzes: !  Five pharmacodynamic (PD) genes !  PD - what the drug does to the body

!  Two pharmacokinetic (PK) genes !  PK - what the body does to the drug

!  Focuses predominantly on neurotransmitter pathways associated with psychiatric disorders.

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!  Role !  Carrier protein found in presynaptic membrane and responsible for

reuptake of 5HT from the synapse1

!  Significance !  The mechanism of action, at least in part, of common antidepressants

including SSRIs, SNRIs, and TCAs involves inhibition of this protein1.

!  Genetic variation determines expression of the serotonin transporter and 5HT reuptake2.

!  The long allele (LA) produces twice the transcription activity as compared to the short allele (S) or (LG)1, and may therefore result in reduced 5HT reuptake1, which is associated with slower response rates and higher incidence of side effects and treatment failure with SSRIs2.

!  The S or LG allele is also associated with higher cortisol burden due to reduced negative feedback on hypothalamic-pituitary-adrenal axis3.

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!  Clinical Significance !  Carriers of S or LG alleles may: !  Be less likely to respond to SSRIs1. !  Respond more slowly to treatment1. !  Experience higher incidence of adverse effects from SSRIs1.

!  Be more likely to develop treatment resistant depression (TRD)4 or post traumatic stress disorder (PTSD)5.

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!  Role !  Regulates entry of calcium and excitatory

neurotransmission into cells6.

!  Significance

!  Mood stabilizers target excitatory neurotransmission7. !  Genetic variation can alter permeability of the channel to

calcium. High permeability of calcium leads to increased sensitivity to depolarization or a reduced action potential threshold8. !  The A allele has been studied in association with

excessive excitatory neurotransmission9.

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!  Clinical Significance !  Carriers of the A allele may: !  Be more likely to have bipolar disease, schizophrenia and

possibly major depressive disorder10-12.

!  Be more likely to experience mood disorder recurrence11.

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!  Role !  G-protein coupled receptor activated by dopamine in the

brain13

!  Significance

!  Antipsychotic medications antagonize this receptor14. !  Genetic variation affects receptor activity and

density14. !  The deletion (Del) allele has been shown to be less

active and correspond to reduced receptor density as compared to the insertion (Ins) allele15. !  The Del allele can significantly influence antipsychotic

drug response14.

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Deletion Insertion

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!  Clinical Significance !  Individuals with the Del allele may: !  Demonstrate less satisfactory antipsychotic drug response

compared to ins/ins individuals14.

!  Be at an increased risk of treatment-emergent side effects from antipsychotics16.

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!  Role !  This enzyme is responsible for degradation of

neurotransmitters including dopamine and norepinephrine17.

!  Significance

!  COMT variants accompanied by reduced dopamine states have been associated with emotional and motivational aspects of behavior18-19. !  Genetic variation may alter dopamine levels. Increased

COMT activity may result in reduced dopamine levels in the brain20.

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!  Clinical Significance !  Individuals who are homozygous for the Val allele may: !  Experience reduced executive brain function including

cognitive and working memory deficits19.

!  Be less likely to respond to SSRI treatments21.

!  Have improved efficiency of pre-frontal cortex information processing in response to amphetamines24.

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!  Role !  Predominant enzyme which converts inactive folic acid to

an active form of folate (methylfolate)20,22.

!  Significance

!  Methylfolate acts as a donor for methylation of DNA, is used to inactivate homocysteine, and is important for neurotransmitter synthesis20,22. !  Genetic variation may alter enzyme function. The T allele

is associated with decreased methylation capacity20,22.

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!  Clinical Significance !  Carriers of T allele may: !  Have reduced dopamine signaling resulting from COMT that

is poorly regulated20. !  Have further exacerbations related to reduced dopamine if

also homozygous for COMT Val variant20.

!  Have an increased association with unipolar depression, anxiety disorders, bipolar disorder, and schizophrenia25.

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!  Role !  Enzymes which metabolize medications in the liver13,16

!  Significance !  A large number of psychiatric medications are substrates

of the 2D6 and 2C19 systems13,16. !  Genetic variants can result in changes in metabolism of

medications13,16. !  Extensive metabolizers (EMs) represent the norm of

metabolic capacity. !  Intermediate metabolizers (IMs) have a reduced metabolic

function (variation in one allele). !  Poor metabolizers (PMs) exhibit a further reduction in

metabolic function (variation in two alleles). !  Ultrarapid metabolizers (UMs) exhibit a higher than average

rate of metabolism. 21 10/28/11 © 2011 Genomind LLC

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!  Clinical Significance !  IMs and PMs may: !  Be at an increased risk of drug-induced side effects and

drug-drug interactions13,16

!  Exhibit an unpredictable response to treatment13,16

!  Require an adjusted dose of medications which are substrates of these systems13,16

!  UMs may: !  Be at higher risk for therapeutic failure due to increased drug

metabolism13,16

!  Be at an increased risk of drug-induced side effects due to increased exposure to drug metabolites13,16

!  Require an adjusted dose of medications which are substrates of these systems13,16

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!  Examples of Substrates

!  CYP2D6 !  venlafaxine, desvenlafaxine, desipramine, nortriptyline,

paroxetine, duloxetine, fluoxetine, risperidone, aripiprazole, haloperidol

!  CYP2C19 !  diazepam, citalopram, escitalopram

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!  Presented at 2011 Autumn Conference of The International Society for CNS Clinical Trials and Methodology (ISCTM)

!  Summary Results !  76% say the Assay influenced their treatment of patients !  67% say they elected to make changes to treatment !  87% say the test increased their confidence in treatment decisions

!  Patients were notable for the severity and chronicity of illness !  39% were reported as having had 4+ previous treatment trials !  More than 1/3 had been ill consistently for more than 4 years

!  Clinicians selected through outreach to members of the Neuroscience Education Institute (NEI)

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!  44 year old divorced male !  Repeated hospitalization over a 2-year period !  Multiple medication failures !  Gene analysis completed by psychiatrist as part of

Genecept Assay pilot launch !  Results of gene analysis displayed variants in

serotonin, dopamine, and metabolism genes !  Psychiatrist confirmed that current medications, which

stabilized patient clinical course, closely matched gene profile and would have significantly reduced trial and error period

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!  Significant research exists surrounding genetic markers associated with psychiatric conditions !  Targeted gene studies !  Genome-wide studies !  Meta-analyses

!  Biomarkers are not intended for diagnosis but can point to compelling biochemical mechanisms involved in causality of psychiatric disorders

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!  Genomind founded to facilitate personalized medicine into psychiatry

!  World-renowned SAB members

!  Genecept Assay and Report beginning commercialization !  Genetic test and analytic report !  Access to pharmacology expertise

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1.  Popp J, Leucht S, Heres S and Steimer W. Serotonin transporter polymorphisms and side effects in antidepressant therapy – a pilot study. Pharmacogenetics 2006;7(2):159-166.

2.  Kato M and Serretti A. Review and meta-analysis of antidepressant pharmacogenetic findings in major depressive disorder. Molecular Psychiatry 2010;15, 473-500.

3.  Way MB and Taylor, SE. The Serotonin Transporter Promoter Polymorphism (5-HTTLPR) is Associated with Cortisol Response to Psychosocial Stress. Biol Psychiatry. 2010 March 1; 67(5): 487–492. doi:10.1016/j.biopsych.2009.10.021.

4.  Bonvicini, C et al. Serotonin transporter gene polymorphisms and treatment-resistant depression. Progress in Neuro-Psychopharmacology & Biological Psychiatry 34 (2010) 934–939.

5.  Grabe, HJ et al. Serotonin Transporter Gene (SLC6A4) Promoter Polymorphisms and the Susceptibility to Posttraumatic Stress Disorder in the General Population. Am J Psychiatry 2009; 166:926–933.

6.  Michel T. Treatment of Myocardial Ischemia. In: Brunton LL, Lazo JS, Parker KL, eds. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 11th ed. New York, NY: McGraw-Hill Book Co; 2006:823-44.

7.  Frankhauser MP and Freeman MP. Bipolar Disorder. In: Pharmacotherapy A Pathophysiolgic Approach. 6th ed. New York, NY: McGraw-Hill Book Co; 2005: 1257-84.

8.  Gargus JJ. Genetic calcium signaling abnormalities in the central nervous system: seizures, migraine, and autism. Ann N Y Acad Sci. 2009 Jan;1151:133-56.

9.  Carroll LS and Owen MJ. Genetic overlap between autism, schizophrenia and bipolar disorder. Genome Med. 2009; 1(10): 102.

10.  Ferreira MA, O’Donovan MC, Meng YA, et al. Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder. Nat Genet. 2008 Sep;40 (9):1056-8.

11.  Green EK, Grozeva D, Jones I, et al. The bipolar disorder risk allele at CACNA1C also confers risk of recurrent major depression and of schizophrenia. Mol Psychiatry. 2010 Oct;15 (10):1016-22.

12.  Nyegaard M, Demontis D, Foldager L, et al. CACNA1C (rs1006737) is associated with schizophrenia. Mol Psychiatry. 2010 Feb;15(2):119-21.

13.  Brunton LB, Lazo JS, Parker KL, eds. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 11th ed. New York: McGraw-Hill; 2005.

14.  Zhang J-P, Lencz T, and Malhotra AK. Dopamine D2 receptor genetic variation and clinical response to antipsychotic drug treatment: A meta-analysis. Am J Psychiatry 2010;167(7):763-772.

15.  Jönsson EG, et al. Polymorphisms in the dopamine D2 receptor gene and their relationships to striatal dopamine receptor density of healthy volunteers. Mol Psychiatry 1999;4(3):290-6.

16.  Fank Gonzalez and Robert Tukey. Drug Metabolism. In: Brunton LL, Lazo JS, Parker KL, eds. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 11th ed. New York, NY: McGraw-Hill Book Co; 2006:71-91.

17.  Baune B. et al. Association of the COMT val158met Variant with Antidepressant Treatment Response in Major Depression. Neuropsychopharmacology 2008;33:924-932.

18.  Kane JM, Perlis RH, Mahatra AK. Clinical insights into pharmacogenetics and schizophrenia, part 2. Journal of Clin Psychiatry. 2008 Jun;69(6):1006-13 19.  Bertolino Alessandro et al. COMT Val158Met polymorphism predicts negative symptoms response to treatment with olanzapine in schizophrenia. Schiz Res 95:253-255 (2007)

20.  Stahl SM. Methylated Spirtis: Epigenetic Hypotheses of Psychiatric Disorders. Trends in Psychopharmacology. CNS Spectr. 15:4 (220-30).

21.  Nnadi CU et al. genetics and Psychopharmacology: Prospects for Indivicdualized Treatment. Essent Psychopharmacol. 2005; 6(4): 193-208.

22.  Methylentetrahydrofolatreductase (MTHFR) A1298C 02-2005, www.genes-4U.com

23.  Wald DS, Law M, and Morris JK. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ 325 : 1202 doi: 10.1136/bmj.325.7374.1202.

24.  Mattay VS et al. Catechol O-methyltransferase val158-met genotype and individual variation in the brain response to amphetamine. PNAS. 2003 May;100(10):6186–6191.

25.  Gilbody S, Lewis S, Lightfoot. Methylenetetrahydrofolate reductase (MTHFR) genetic polymorphisms and psychiatric disorders: a HuGE review. Am J Epidemiol. 2007 Jan 1;165(1):1-13. Epub 2006 Oct 30.

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