20180202 3 j. lombard genomind milan relazione part 2 to pub.pptx
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https://www.linkedin.com/pulse/simposio-toma-implementazione-della-farmacogenetica-nel-scarafia/ https://www.linkedin.com/pulse/malattie-psichiatriche-e-neurologiche-arriva-toma-il-test-scarafia/ 2 febbraio 2018, Sala Congressi Laboratorio TOMA Relatori: Dr. J. Lombard, Dr.ssa F.R. Grati, Dr.ssa S. De Toffol BREVE PREMESSA La farmacogenetica studia l’influenza dei fattori genetici sull’attività di un farmaco, la sua assimilazione e il suo metabolismo allo scopo di massimizzarne l’efficacia terapeutica e minimizzare gli effetti avversi. I fattori genetici possono giustificare fino al 95% della variabilità interpersonale nella risposta e nelle reazioni avverse a determinati trattamenti farmacologici. Finora la diagnosi ed il trattamento farmacologico in psichiatria si sono basati principalmente sul un protocollo ‘trial and error’ tramite colloquio, osservazione clinica e analisi di laboratorio costituivano esclusivamente un complemento per valutare possibili effetti collaterali o i livelli plasmatici di alcuni farmaci. L’introduzione di test di farmacogenetica consente di fornire al clinico informazioni costitutive dell’individuo relativamente al metabolismo di molti farmaci e la potenziale risposta in determinati contesti clinici al fine di ridurre i tempi ottenimento del trattamento efficace personalizzato e arricchire con le più recenti informazioni genetiche la gestione terapeutica dei pazienti. OBIETTIVI FORMATIVI Introdurre i principi scientifici alla base del test genetico che si presenterà durante il corso, il significato, la funzione e la rilevanza clinica per la salute mentale di ciascun gene indagato dal test; L’utilità clinica del test Genecept: presentare come vengono riportati i risultati del test e come meglio interpretarli; Presentare alcuni casi clinici reali per discutere circa l’utilità di un trattamento farmacologico guidato dai risultati del test genetico rispetto all’approccio tradizionale ‘trial and error’
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20180202 3 j. lombard genomind milan relazione part 2 to pub.pptx
- 1. Implementing Pharmacogenetic Testing for Mental Health Illness: How brain biology informs and advances treatment opportunities
- 2. Treatment as Usual 27% 16% 41% 15% 30% 66% 44% 77% 25% 37% 0% 20% 40% 60% 80% 100% ADHD Schizophrenia Bipolar Disorder Anxiety Depression Initial Remission Rate Range Treatment Resistance / Relapse 50% of patients do not respond to first-line therapies or experience severe adverse reactions 30% treatment resistant following 4 treatments 1 Recurrence in up to 50% 5,6 50-70% relapse rates 2,4 >75% of patients discontinued medication within 18 months 3 ADHD can persist in about 65% of adults diagnosed as children 7 STAR-D: NIMH; STEP-BD: NIMH; Angst et al. (2009); Yonkers et al. (1996);CATIE:NIMH; Perry et al. (1999); Faraone et al. (2006)
- 3. Treatment Resistance: Depression 36,8% 30,6% 13,7% 13,0% 16,3% 19,5% 25,6% 34,1% 0% 5% 10% 15% 20% 25% 30% 35% 40% 1 2 3 4 TREATMENT TRIAL STAR-D Remission & Intolerance Rates Remission Rates Intolerance Rates Rush et al. (2006)
- 4. § Founded in 2009 to improve therapeutics in neuropsychiatry § Co-founders: Dr. Ronald Dozoretz and Dr. Jay Lombard § Developed and commercialized the Genecept Assay™, a patent- protected, saliva-based genetic test that informs clinician treatment decisions for patients with psychiatric conditions § State-of-the-art CLIA , CAP, New York licensed accredited lab § Future R&D dedicated to being a leader in bringing personalized medicine to neuropsychiatry by translating cutting edge science and research to the clinic § Over 100k samples commercially run since launch Data on file. Genomind 2016.
- 5. To improve the lives of patients with mental illness by bringing innovative technologies to clinical care Genomind’s Mission
- 6. Evidence Base of the Genecept Assay § Inclusion of genes in the panel is supported by strong peer reviewed literature • Genomind’s clinical team, working closely with our SAB, assesses the strength of the data • Genes were selected based on the critical examination of hundreds of studies showing that variations in these genes can inform treatment decisions § Report content is fully cited, with 200 references to date § Genomind has developed a full Literature Summary, summarizing each citation related to the genetic variations analyzed Data on file. Genomind 2016.
- 7. Scientific Advisory Board Scott T. Anderson, MD Clinical Assistant Professor of Psychiatry at the University of Maryland School of Medicine and Distinguished Fellow of the American Psychiatric Association. Associate Medical Director and Director of Clinical Research at The Retreat at Sheppard Pratt. P. Murali Doraiswamy, MD Professor in the department of psychiatry at Duke University Medical Center. He is also a professor in medicine at Duke University and a member of the Duke Institute for Brain Sciences. He also serves as a brain health advisor for Men’s Health magazine. Maurizio Fava, MD Executive Vice Chair of the Department of Psychiatry at the Massachusetts General Hospital. He also serves as Executive Director, Clinical Trials Network and Institute (CTNI); Director, Depression Clinical and Research Program (DCRP) at the MGH and is the Slater Family Professor of Psychiatry at Harvard Medical School. Anil Malhotra, MD Director of Psychiatry Research at the Zucker Hillside Hospital in Glen Oaks, NY, Professor of Psychiatry and Behavioral Sciences at the Albert Einstein College of Medicine (AECOM) in the Bronx, NY, and an Investigator at the Feinstein institute for Medical Research in Manhasset, NY. Roy H. Perlis, MD, MSc Director of the Center for Experimental Drugs and Diagnostics, Massachusetts General Hospital Department of Psychiatry and an Associate Professor at Harvard Medical School. Stephen M Stahl, MD, PhD Adjunct Professor of Psychiatry at the University of California, San Diego and Honorary Visiting Senior Fellow, University of Cambridge, U.K. He has held faculty positions at Stanford University, the University of California, Los Angeles, the Institute of Psychiatry London and the Institute of Neurology London. Dr. Stahl was also Executive Director of Clinical Neurosciences at the Merck Neuroscience Research Center in the U.K. for several years. Rudolph E. Tanzi, PhD Director of the Genetics and Aging Research Unit at the Massachusetts General Institute for Neurodegenerative Disease in Boston. He is also a professor of neurology and holder of the Joseph P. and Rose F. Kennedy Endowed Chair in Neurology and Mental Retardation at Harvard University.
- 8. 18 Genes: Kinetic vs. Dynamic 6 Pharmacokinetic Genes: CYP3A4/5 CYP2D6 CYP2C19 CYP1A2 CYP2B6 CYP2C9 12 Pharmacodynamic Genes: SLC6A4 COMT ADRA2A DRD2 CACNA1C ANK3 MC4R 5HT2C OPRM1 GRIK1 MTHFR BDNF Häggström, Mikael (2014)
- 9. 18 Actionable Genetic Variants SLC6A4 Serotonin Transporter Use caution with SSRIs; Atypical antidepressants or SNRIs may be used if clinically indicated CACNA1C Calcium Channel Atypical antipsychotics, mood stabilizers, and/or omega-3 fatty acids, which may help reduce excitatory signaling may be used clinically if indicated ANK3 Sodium Channel Mood stabilizers, and/or omega-3 fatty acids, which may help reduce excitatory signaling may be used clinically if indicated 5HT2C Serotonin Receptor 2C Use caution with atypical antipsychotics; Inositol may be used to mitigate risk for weight gain if clinically indicated MC4R Melanocortin 4 Receptor Use caution with atypical antipsychotics DRD2 Dopamine 2 Receptor Use caution with antipsychotics COMT Catechol-O- Methyltransferase Dopaminergic agents or TMS may be used if clinically indicated for Val/ Val patients; Use caution with dopaminergic agents in Met/Met patients ADRA2A Alpha-2A Adrenergic Receptor Stimulant agents may be used if clinically indicated MTHFR Methylenetetrahydrofolate Reductase Supplementation with L- methylfolate may be used if clinically indicated BDNF Brain-derived Neurotrophic Factor Increased physical activity / exercise may be beneficial for Met carriers if clinically indicated OPRM1 µ-Opioid Receptor Use caution with opioid; non- opioid analgesics may be used if clinically indicated GRIK1 Glutamate Receptor Topiramate may be used for treatment of alcohol abuse if clinically indicated A1298C | C677T CYP1A2 CYP2B6 CYP2C9 CYP2C19 CYP2D6 CYP3A4/5 Dose adjustment (an increase of decrease) may be required Pharmaco-kineticPharmaco-dynamic
- 10. Genetics 101
- 11. Nature AND Nurture GENES Environment Phenotype § In psychiatry we do a good job of determining what environmental factors have contributed to a particular disorder § Until now, we have not had access to a large component of our phenotype…..genetic factors GENECEPT ASSAY Patient History Personalized Treatment = =
- 12. Base Pairs and SNPs NHS National Genetics and Genomics Education Centre (2014)Karonlin, V. (2015) C>T substitution
- 13. Types of Genetic Variation MTHFR: C/T DRD2: C/DEL SLC6A4: L/S COMT: VAL/VAL Homozygous Heterozygous • Heterozygous: non-identical alleles • Homozygous: identical alleles
- 14. Gene X Environment Interaction Lok et al. (2013) 1 4 MTHFR CC CT ----------------- TT ------------------
- 15. Genecept Assay Genes in Detail: Pharmacokinetic Variants
- 16. CYP450 Variations § Gene variants associated with altered liver enzyme metabolism activity may lead to side effects and toxicity IM PM Poor metabolizers or inhibitors of P450 may have increased drug serum levels and adverse events. IM Intermediate metabolizers or inhibitors of P450 may have increased drug serum levels and adverse events. EM Extensive metabolizers metabolize substrates normally. UM Ultra-rapid metabolizers or inducers of P450 may have reduced drug serum levels and poor efficacy. 16 FDA warning (Aug 2011): Citalopram maximum dose of 20mg in CYP2C19 poor metabolizers and those receiving CYP2C19 inhibitors Swen et al 2011; FDA (2012)
- 17. CYP450 Substrates • Antidepressants: Duloxetine, Escitalopram, Fluoxetine, Fluvoxamine, Mirtazapine, Paroxetine, TCA’s, Venlafaxine*, Vortioxetine, Nefazodone • Antipsychotics: Aripiprazole, Brexpiprazole, Clozapine, Iloperidone, Olanzapine, Risperidone, Chlorpromazine, Fluphenazine, Haloperidol, Perphenazine, Pimozide, Thioridazine • Stimulants/NRI: Amphetamine, Methamphetamine, Atomoxetine • Pain: Codeine*, Hydrocodone*, Oxycodone, Tramadol • Anxiolytic/Misc: Propranolol, Clonidine CYP2D6 • Antidepressants: Citalopram, Escitalopram, Amitriptyline, Clomipramine, Imipramine, Trimipramine, Venlafaxine* • Pain: Carisoprodol • Anxiolytic: Diazepam, Propranolol • Sleep: Suvorexant CYP2C19 *pro-drug conversion
- 18. CYP450 Substrates • Antidepressants: Citalopram, Levomilnacipran, Mirtazapine, Trazodone, Trimipramine, Vilazodone, Nefazodone • Mood Stabilizer: Carbamazepine • Miscellaneous stimulants: Armodafinil, Guanfacine, Modafinil • Anxiolytic: Alprazolam, Buspirone, Chlordiazepoxide, Clonazepam, Diazepam • Pain: Alfentanil, Fentanyl, Methadone, Oxycodone, Tramadol, Meperidine, Buprenorphine • Antipsychotics: Aripiprazole, Brexpiprazole, Cariprazine, Clozapine, Lurasidone, Quetiapine, Haloperidol, Pimozide • Sleep: Zolpidem, Zaleplon, Eszopiclone, Suvorexant CYP3A4 CYP3A5
- 19. CYP450 Substrates • Antidepressants: Clomipramine, Duloxetine, Fluvoxamine, Mirtazapine • Antipsychotics: Asenapine, Clozapine, Olanzapine, Thiothixene, Trifluoperazine • Pain: Cyclobenzaprine, Tizanidine, Naproxen • Anxiolytic: Propranolol • Sleep: Ramelteon CYP1A2 • Antidepressants: Fluoxetine • Mood Stabilizers: Valproate • Pain: Celecoxib, Diclofenac, Flurbiprofen, Meloxicam, Piroxicam, NaproxenCYP2C9 • Antidepressants: Bupropion*, Selegiline • Pain: Methadone, Meperidine CYP2B6 *pro-drug conversion
- 22. CYP1A2: Gene X Environment § CYP1A2 is induced by certain environmental factors • CYP1A2 levels will be increased with smokers - Tobacco - Marijuana Zhou et al. (2009); Gunes and Dahl (2008) CYP1A2 *1F/*1F is a particularly inducible gene variant
- 23. Genecept Assay Genes in Detail: Pharmacodynamic Variants
- 24. Serotonin Transporter (SLC6A4) § SLC6A4 is reported as L(A) (normal) or L(G) or S (risk) § Patients carrying the S or L(G) allele are at higher risk for side effects and/or lack of response to SSRIs Clinical Impact: § Caution with SSRIs § Therapeutic Options: SNRIs and Atypical Antidepressants Kato and Serretti (2010); Porcelli et al. (2012)
- 25. SLC6A4 Genotypes L(A)/ L(A) • Higher response/ remission rates to SSRIs • Lower adverse event rates to SSRIs L/S • Higher adverse event rates to SSRIs • Response rates mostly unchanged S/S L(G)/ L(G) • Lower response/ remission rates to SSRIs • Elevated stress induced cortisol • Higher adverse event rates to SSRIs SLC6A4 Porcelli et al. (2012); Hu et al. (2007) Chromosome 17
- 26. Symptoms MDD episode Suicidality MDD/Informant SLC6A4 Gene X Environment Caspi et al. (2003)
- 28. Neuronal Ion Channels and Psychiatric Disorders Activating GLU receptors leads to depolarization as Na+ enters the cell. Depolarization opens Ca++ channels which are responsible for neurotransmitter release GLU Na+ Ligand gated Na+ channel Voltage gated Na+ channel Ca++ Voltage gated Ca++ channel Na+Na+ § Homozygotes of the ANK3 ‘T’ allele or CACNA1C ‘A’ allele are at higher risk of altered neuronal signaling § Clinical Impact: therapeutic options include agents that reduce neuronal signaling such as mood stabilizers, atypical antipsychotics, omega 3 fatty acids Ferreira et al., 2008
- 29. Serotonin 2C (5HT2C) & Melanocortin 4 Receptor (MC4R) 2 9 Sicard et al. (2010); Malhotra et al. (2012) Lower Risk WEIGHT GAIN Higher risk 5HT2C “T” carrier MC4R “A/A” genotype ~5-15% of patients ~5-25% of patients Atypical Antipsychotic
- 30. Results Report – 5HT2C and MC4R § Use caution with atypical antipsychotics (weight gain, NOT efficacy) § High risk medications: clozapine and olanzapine § Medium risk medications: aripiprazole; iloperidone; paliperidone; quetiapine; risperidone § Low risk medications: asenapine; cariprazine; brexpiprazole; lurasidone; ziprasidone § Metformin, Lorcaserin or other anti-obesity interventions
- 31. Dopamine Receptor (DRD2) § Deletions (DEL) in the dopamine receptor gene can alter receptor density leading to poorer outcomes with atypical and typical antipsychotics. § Indicates that antipsychotics are less likely to be effective and more likely to cause weight gain § Meta analysis showed an increased risk of opiate abuse with (DEL) carriers Clinical Impact: Use with caution or alternative agent § Antipsychotic clinical efficacy is highly correlated with the binding affinity to the Dopamine 2 Receptor Zang et al 2010; Chen et al. (2011)
- 32. Catechol-o-methyltransferase (COMT) COMT graphic; Barnett et al. (2007); Hamidovic et al, (2010) Schacht (2016) § COMT is the primary enzyme responsible for dopamine degradation in the prefrontal cortex § COMT VAL158MET gene can identify the two extremes of dopamine metabolism COMT Activity DA Levels Clinical Impact High (Val/Val) Low • Impaired working memory • Higher response with dopaminergic stimulants • Cognitive improvement with COMT inhibitors Low (Met/Met) High • Improved working memory • Lower response to dopaminergic stimulants • Improved response to SGAs Val/ValMet/Met
- 33. COMT & Methylphenidate Response 87% 13% Val/Val Responders Non-Responders 71% 29% Val/Met Responders Non-Responders 58% 42% Met/Met Responders Non-Responders Kereszturi et al. (2008) § Response rates to methylphenidate for ADHD treatment vary based on COMT genotype
- 34. 34
- 35. 35 Response rates with Genecept Assay are comparable regardless of the number of failed treatment trials 16% 17% 29% 49% 56% 75% 66% 69% 55% 59% 5+ failed trials (n = NA / 181) 4 failed trials (n = NA / 75) Level 4 (n = 123 / 79) Level 3 (n = 390 / 94) Level 2 (n = 1,493 / 103) Level 1 (n = 3,671 / 93) Response Rates by Treatment Trials1,2 Genecept (Clinician reported) STAR*D Response rates with Genomind exceed those reported in the seminal STAR*D trials On average… 63%of patients across all levels of treatment resistance receiving Genecept-guided treatment showed a clinically significant response 1) Levels indicate either stages of treatment in STAR*D or number of previously failed adequate treatment trials, with level 1 indicating zero previous treatment trials 2) Response measured by ≥ 50% reduction in QIDS-SR16 (STAR*D) or CGI-I of 1 or 2 (Genecept™-Clinician Reported)
- 36. 36 Clinicians report clinical improvement in majority of patients tested with Genecept 0% 2% 11% 25% 43% 19% 6 - Much worse 5 - Minimally worse 4 - No change 3 - Minimally improved 2 - Much improved 1 - Very much improved Patients with measurable clinical improvement – clinician assessedⱡ All patients (n = 625) 1 Brennan FX et al. Prim Care Companion CNS Disord. 2015; 17(2). 87%of all patients receiving Genecept-guided treatment* showed clinically-measurable improvement * In an open label clinical study1 examining the effectiveness of genetic testing with the Genecept Assay ⱡ Clinicians used the Clinical Global Impressions—Severity of Illness (CGI-S) scale for disease severity to assess improvement
- 37. 37 Clinicians also report clinical improvement in treatment-resistant patients tested with Genecept 0% 2% 7% 27% 44% 20% 6 - Much worse 5 - Minimally worse 4 - No change 3 - Minimally improved 2 - Much improved 1 - Very much improved Patients with measurable clinical improvement – clinician assessedⱡ Treatment-resistant patients (n = 429) 1 Brennan FX et al. Prim Care Companion CNS Disord. 2015; 17(2). 91%of treatment-resistant patients (i.e. those with 2 or more failed medication trials) receiving Genecept-guided treatment* showed clinically- measurable improvement * In an open label clinical study1 examining the effectiveness of genetic testing with the Genecept Assay ⱡ Clinicians used the Clinical Global Impressions—Severity of Illness (CGI-S) scale for disease severity to assess improvement
- 38. 38 The Genecept Assay influences clinician decision- making for patients with mental health conditions 0% 10% 20% 30% 40% 50% 60% 70% Definitely Yes Probably Yes Probably Not Definitely Not Don't Know Influence of the Genecept Assay on Clinician Decision-Making Did the assay influence medication decisions? Did the assay influence confidence in medication decisions? 1 Brennan FX et al. Prim Care Companion CNS Disord. 2015; 17(2). Clinicians made a change to the medication regimen congruent with the assay report for 94% of patients94% >90%of clinicians reported that the Genecept Assay had an impact on their treatment decisions (n = 42 clinicians completing assessments regarding 625 patients in an open label clinical study1 examining the effectiveness of genetic testing with the Genecept Assay)
- 39. 39
- 40. Case Study § 42 y/o male, fully employed with 2 children § Chronic diagnosis of MDD for more than 20 years § Presents with refractory depression, thoughts of sadness and suicidal ideation and mood swings § Fluoxetine and escitalopram led to minimal improvement of symptoms, d/c due to inefficacy and/ or side effects
- 41. Case Study § What would your treatment choice be? § Sertraline § Duloxetine § Bupropion § Mood stabilizer § Methylfolate Currently taking no meds, but admits to periodic ETOH binge use
- 42. Patient Results Data on file. Genomind 2016.
- 43. Patient Results Data on file. Genomind 2016.
- 44. Patient Results Data on file. Genomind 2016.
- 45. Patient Results Data on file. Genomind 2016.
- 46. Interpretation Data on file. Genomind 2016. Cymbalta added. Risk of induction only in presence of inducers (smoking)
- 47. Interpretation § L-methylfolate and Omega-3 fatty acids were also added to the patients regimen due to the presence of variations in MTHFR and CACNA1C § Also began exercise regimen BDNF MET Data on file. Genomind 2016.
- 48. Interpretation Data on file. Genomind 2016. Latuda added. Low weight gain risk. Normal metabolizer. COMT MET/MET
- 49. Follow-up § Patient reported § Stable mood, with no new depressive episodes § No sexual side effects § Reduction of HAM-D from 20 to 5 § Reduction of depressive thoughts, suicidal ideation, and mood swings has allowed him to become more productive in work and in his social life
- 50. Case Study § 34 year old, female, history of depression, anxiety, poor focus § Was on stimulants as a child, takes episodically Adderall when under stress § Presents with recent onset of sleep difficulty, anxiety poor concentration and depression § Current medications, birth control pill, Lexapro, Klonopin PRN
- 51. Interpretation Data on file. Genomind 2016.
- 52. Interpretation Data on file. Genomind 2016.
- 53. Interpretation Data on file. Genomind 2016.
- 54. Interpretation Data on file. Genomind 2016.
- 55. Follow-up § Patient reported § Recommendations to taper Lexapro and start mixed Serotonin/ Norepinephrine reuptake inhibitor § Start patient on Pristiq, (Lexapro 2C19 metabolized drug) § Add methlyfolate § Consider continuous use of low dose stimulant § Reduction of depressive symptoms, improved sleep
- 56. Discover the Genecept Assay www.genomind.com