Personalized Medicine           And The Science Behind            The Genecept Assay           TM                Jay Lomba...
!    Genomind Chief Scientific Officer and Chief     Medical Officer!    Nationally recognized leader in neuropsychiatry  ...
!    Treatment efficacy is often unsatisfactory with high rates     of side effects and incomplete remission in many     p...
!    The assay analyzes:        !  Five pharmacodynamic (PD) genes            !  PD - what the drug does to the body      ...
10/28/11   © 2011 Genomind LLC   References on slide 30   5
!    Role      !  Carrier protein found in presynaptic membrane and responsible for         reuptake of 5HT from the synap...
10/28/11   © 2011 Genomind LLC   References on slide 30   7
!    Clinical Significance     !  Carriers of S or LG alleles may:      !  Be less likely to respond to SSRIs1.      !  Re...
!    Role     !  Regulates entry of calcium and excitatory        neurotransmission into cells6.!    Significance     !  M...
10/28/11   © 2011 Genomind LLC   References on slide 30   10
!    Clinical Significance      !  Carriers of the A allele may:          !  Be more likely to have bipolar disease, schiz...
!    Role     !  G-protein coupled receptor activated by dopamine in the        brain13!    Significance     !  Antipsycho...
Deletion                  Insertion10/28/11       © 2011 Genomind LLC   References on slide 30   13
!    Clinical Significance      !  Individuals with the Del allele may:          !  Demonstrate less satisfactory antipsyc...
!    Role     !  This enzyme is responsible for degradation of        neurotransmitters including dopamine and        nore...
10/28/11   © 2011 Genomind LLC   References on slide 30   16
!    Clinical Significance      !  Individuals who are homozygous for the Val allele may:          !  Experience reduced e...
!    Role     !  Predominant enzyme which converts inactive folic acid to        an active form of folate (methylfolate)20...
10/28/11   © 2011 Genomind LLC   References on slide 30   19
!    Clinical Significance      !  Carriers of T allele may:          !  Have reduced dopamine signaling resulting from CO...
!    Role     !  Enzymes which metabolize medications in the liver13,16!    Significance     !  A large number of psychiat...
!    Clinical Significance      !  IMs and PMs may:          !  Be at an increased risk of drug-induced side effects and  ...
!    Examples of Substrates      !  CYP2D6          !  venlafaxine, desvenlafaxine, desipramine, nortriptyline,           ...
!    Presented at 2011 Autumn Conference of The International     Society for CNS Clinical Trials and Methodology (ISCTM)!...
!  44 year old divorced male!  Repeated hospitalization over a 2-year period!  Multiple medication failures!  Gene analysi...
10/28/11   © 2011 Genomind LLC   26
!    Significant research exists surrounding genetic     markers associated with psychiatric conditions      !  Targeted g...
10/28/11   © 2011 Genomind LLC   28
!    Genomind founded to facilitate personalized     medicine into psychiatry!    World-renowned SAB members!    Genecept ...
1.        Popp J, Leucht S, Heres S and Steimer W. Serotonin transporter polymorphisms and side effects in antidepressant ...
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Personalized Medicine and Science of the Genecept Assay

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From the webinar, "Learn How Genetic Testing Can Help Inform Your Neuropsychiatric Treatment Decisions," presented by Dr. Jay Lombard, Chief Scientific Officer of Genomind, LLC.

Dr. Lombard discusses scientific, clinical, and research aspects regarding the pharmacodynamic and pharmacokinetic genes in the Genecept™ Assay - genes that influence neurotransmitter activity and treatment plans for neuropsychiatric disorders. He discusses recent developments in the science of biomarkers for dopamine and serotonin, as well as genes that affect drug metabolism in the body.

The Genecept Assay is Genomind's proprietary genetic test that offers the possibility of "Personalized Medicine" in psychiatry. Clinicians may find this additional genetic information can lead to optimized treatment plans for individual patients.

Genomind is a company specializing in neuropsychiatric personalized medicine and was formed to facilitate the adoption of personalized medicine into psychiatry by providing genetic information to better understand the patient.

For more information, please visit our website at www.genomind.com.

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Personalized Medicine and Science of the Genecept Assay

  1. 1. Personalized Medicine And The Science Behind The Genecept Assay TM Jay Lombard, DO October 28, 201110/28/11 © 2011 Genomind LLC 1
  2. 2. !  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. 10/28/11 © 2011 Genomind LLC 2
  3. 3. !  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 10/28/11 © 2011 Genomind LLC 3
  4. 4. !  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. 10/28/11 © 2011 Genomind LLC 4
  5. 5. 10/28/11 © 2011 Genomind LLC References on slide 30 5
  6. 6. !  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. 10/28/11 © 2011 Genomind LLC References on slide 30 6
  7. 7. 10/28/11 © 2011 Genomind LLC References on slide 30 7
  8. 8. !  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. References on slide 30 8
  9. 9. !  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. 10/28/11 © 2011 Genomind LLC References on slide 30 9
  10. 10. 10/28/11 © 2011 Genomind LLC References on slide 30 10
  11. 11. !  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. 10/28/11 © 2011 Genomind LLC References on slide 30 11
  12. 12. !  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. 10/28/11 © 2011 Genomind LLC References on slide 30 12
  13. 13. Deletion Insertion10/28/11 © 2011 Genomind LLC References on slide 30 13
  14. 14. !  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. 10/28/11 © 2011 Genomind LLC References on slide 30 14
  15. 15. !  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. 10/28/11 © 2011 Genomind LLC References on slide 30 15
  16. 16. 10/28/11 © 2011 Genomind LLC References on slide 30 16
  17. 17. !  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. 10/28/11 © 2011 Genomind LLC References on slide 30 17
  18. 18. !  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. 10/28/11 © 2011 Genomind LLC References on slide 30 18
  19. 19. 10/28/11 © 2011 Genomind LLC References on slide 30 19
  20. 20. !  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. 10/28/11 © 2011 Genomind LLC References on slide 30 20
  21. 21. !  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 10/28/11 rate of metabolism. © 2011 Genomind LLC References on slide 30 21
  22. 22. !  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 10/28/11 © 2011 Genomind LLC References on slide 30 22
  23. 23. !  Examples of Substrates !  CYP2D6 !  venlafaxine, desvenlafaxine, desipramine, nortriptyline, paroxetine, duloxetine, fluoxetine, risperidone, aripiprazole, haloperidol !  CYP2C19 !  diazepam, citalopram, escitalopram 10/28/11 © 2011 Genomind LLC References on slide 30 23
  24. 24. !  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) 10/28/11 © 2011 Genomind LLC 24
  25. 25. !  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 period10/28/11 © 2011 Genomind LLC 25
  26. 26. 10/28/11 © 2011 Genomind LLC 26
  27. 27. !  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 10/28/11 © 2011 Genomind LLC 27
  28. 28. 10/28/11 © 2011 Genomind LLC 28
  29. 29. !  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 10/28/11 © 2011 Genomind LLC 29
  30. 30. 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 Gilmans 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 & Gilmans 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 Gilmans 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):1006-1319.  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.com23.  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. 10/28/11 © 2011 Genomind LLC 30
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