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PGXL Psychiatry Panels Kristen K. Reynolds, PhD VP Laboratory Operations Copyright 2012 PGXL Laboratories, Louisville KY All materials herein are the exclusive property of PGXL Laboratories Building Better Panels • Targeted panels that maximize guidance for drug selection and dose • Metabolism targets: dose and adverse event risk • Receptor targets: drug choice CYP2D6 and serotonin transporter variants alter drug dose and/or selection SSRI Antidepressants PD Response SLC6A4 Dependent on drug concentration, receptor expression and affinity PK Metabolism PMs CYP2D6 EMs UMs Ramey-Hartung, El-Mallakh, Reynolds. Clin Lab Med 2008;28:627-43. X Clearance Application of Pharmacogenetics to behavioral health PGXL Psych Panels* PGXL Depression Panel STA2R Panel = Psychosis • • • • • • • • • • • • • • • 2D6 2C19 2C9 1A2 3A4 3A5 Add on: SLC6A4 *updated as of 11-20-12 SULT4A1:olanzapine 2D6 2C19 2C9 1A2 3A4 3A5 SLC6A4 PGXL Psychiatry Panels – Metabolic Routes PSYCHIATRY Antidepressants Antipsychotics, Mood Stabilizers Generic Amitriptyline Bupropion Citalopram Clomipramine Brand Various brands Wellbutrin Celexa Ananfranil Metabolic Route CYP2D6 CYP1A2, (CYP2B6) CYP2C19 CYP2D6, CYP1A2 Desipramine Desvenlafaxine Doxepin Duloxetine Escitalopram Fluoxetine Fluvoxamine Imipramine Norpramin Pristiq Sinequan Cymbalta Lexapro, various Prozac Luvox Tofranil Maprotiline Mianserin Mirtazapine Nefazadone Nortriptyline Ludiomil Various brands Remeron Serzone Pamelor, Aventyl Paroxetine Reboxetine Sertraline Trazadone Trimipramine Venlafaxine Paxil Edronax Zoloft Desyrel Surmontil Effexor CYP2D6 CYP3A4/CYP3A5 CYP2D6 CYP2D6, CYP1A2 CYP2C19 CYP2D6 CYP2D6 CYP2D6, CYP2C19, CYP1A2 CYP2D6 CYP2D6, CYP1A2 CYP2D6, CYP1A2 CYP3A4/CYP3A5 CYP2D6, CYP3A4/CYP3A5 CYP2D6 CYP3A4/CYP3A5 CYP2C19 CYP3A4/CYP3A5 CYP2D6 CYP2D6 Generic Alprazolam Amphetamine Aripiprazole Asenapine Atomoxetine Buspirone Carbamazepine Chlorpromazine Clozapine Diazepam Haloperidol Iloperidine Lurasidone Brand Xanax Adderall Abilify Saphris Strattera Buspar Various brands Thorazine Clozaril Valium Haldol Fanapt Latuda Metabolic Route CYP3A4/CYP3A5 CYP2D6 CYP2D6 CYP1A2 CYP2D6 CYP3A4/CYP3A5 CYP3A4/CYP3A5 CYP2D6 CYP1A2 CYP2C19 CYP2D6 CYP2D6 CYP3A4/CYP3A5 Midazolam Olanzapine Perphenazine Promazine Quetiapine Versed Zyprexa Trilafon Sparine Seroquel CYP3A4/CYP3A5 CYP1A2 CYP2D6 CYP1A2 CYP3A4/CYP3A5 Risperidone Thioridazine Triazolam Ziprasidone Zuclopenthixol Risperidol Mellaril Halcion Geodon Various brands CYP2D6 CYP2D6 CYP3A4/CYP3A5 CYP3A4/CYP3A5 CYP2D6 Genotype Frequency % Gene EM IM PM UM 2D6 53 35 10 2 2C19 36 32 4 28 2C9 57 40 3 NA 3A4 87 12 1 NA 3A5 1 18 81 NA 2D6 Atomoxetine PMs • 4x longer to SS • 4x higher drug levels • 4x longer to wash-out • More likely to have AE Plasma atomoxetine (ng/mL) 2600 20 mg q12h PM 2080 7 2 h rs 1560 1040 EM 520 0 0 24 48 72 96 120 144 168 192 216 240 264 Time (hrs) S S ;E M S S ;P M 2D6 Paroxetine P aroxetine A ccumulation (20 mg q 24 hr) Plasma paroxetine (ng/mL) 70 PM 56 144 hr 42 28 EM 14 0 0 92 184 276 S S ;P M S S ;E M Tim e (hr s) 368 460 CYP2D6 *4/*4 CYP2D6 Phenotype THERAPEUTIC IMPLICATIONS (adapted from published resources) Poor Metabolizer Avoid Codeine** Hydrocodone** Oxycodone** Tramadol** Tamoxifen** Amitriptyline † Venlafaxine † Risperidone † Alternative Consideration Adjust Dosage Adjustment Morphine, non-opioid Hydromorphone, non-opioid Oxymorphone, non-opioid Consider active drug, non-opioid Anastrozole, exemestane, letrozole Citalopram, sertraline Citalopram, sertraline Quetiapine, olanzapine, clozapine Aripiprazole † 10 mg/day maximum decrease 50% decrease 60% decrease 50% decrease 50% decrease 70% decrease 60% decrease 70% decrease 75%, or atenolol, bisoprolol, carvedilol decrease 50%, or flupenthixol, quetiapine, olanzapine, clozapine Clomipramine † Doxepin † Flecainide † Haloperidol † Imipramine† Nortriptyline † Propafenone † Metoprolol † Zuclopenthixol † **Lack of efficacy due to failure to produce active metabolite; †Increased risk of adverse events due to diminished drug clearance. CYP2D6 Poor Metabolizer (PM): This patient’s genotype is consistent with a lack of CYP2D6 enzymatic activity. PMs are at increased risk of drug-induced side effects due to diminished drug elimination of active drugs or lack of therapeutic effect resulting from failure to generate the active form of the drug, as is the case with pro-drugs. CONFIDENTIAL COPYRIGHT PGXL LABORATORIES 2012 Drug selection “algorithm” using CYPs CONFIDENTIAL COPYRIGHT PGXL LABORATORIES 2012 SLC6A4 add-on Serotonin Transporter SLC6A4 • 50-60% depressed patients have recurrence and 20% fail 1st line Rx (SSRIs) – TRD increased # of Rx, hospitalization risk, costs (19x higher) • 75% people carry S or LG • S/S, S/LG, or LG/LG should be considered for non-SSRI therapies SLC6A4 interpretations SLC6A4 Phenotype Normal Responder SLC6A4 Phenotype Intermediate Responder SLC6A4 Phenotype Poor Responder THERAPEUTIC IMPLICATIONS (adapted from published resources) Normal serotonin transporter expression expected. Patients with the LA/LA genotype are more likely to respond within the first 4 weeks of therapy, achieve remission, and are less likely to have adverse effects when treated with SSRIs. THERAPEUTIC IMPLICATIONS (adapted from published resources) Carriers of S or LG alleles may have decreased serotonin transporter expression compared to LA/LA subjects. Possible risk of decreased or slower response to SSRIs or increased risk of adverse events. THERAPEUTIC IMPLICATIONS (adapted from published resources) Decreased serotonin transporter expression expected. Risk of decreased response to SSRI-based therapies and increased risk of adverse events. Consider non-SSRI antidepressant therapies, such as SNRIs or tricyclic antidepressants alternatives. Antidepressants 2C19 2C19 2D6 2D6,1A2 2D6 2C19 3A4/5 SSRIs citalopram escitalopram fluoxetine fluvoxamine paroxetine sertraline vilazodone Celexa Lexapro Prozac Luvox Paxil Zoloft Viibryd 2D6,1A2,3A4/5 2D6,1A2 2D6,2C19 2D6 2D6 2D6,3A4/5 2D6,3A4/5,2C19 TCAs amitriptyline clomipramine desipramine doxepin imipramine nortriptyline trimipramine Elavil Anafranil Norpramin Sinequan Tofranil Pamelor, Aventyl Surmontil 2C19 MAOIs phenelzine tranylcyromine isocarboxazid moclobemide Nardil Parnate Marplan Black, major pathway; gray, minor pathway SNRIs 2D6,1A2 duloxetine 2D6 venlafaxine 3A4/5 desvenlafaxine renal milnacipran 2D6,1A2,3A4/5 mirtazapine 2B6,1A2 3A4/5 3A4/5 2D6 2D6,1A2 3A4/5 Cymbalta Effexor Pristiq Savella Remeron Atypicals (NRIs, NDRIs) bupropion Wellbutrin trazadone Desyrel nefazadone Serzone maprotiline Ludiomil mianserin reboxetine Edronax PGXL Depression Panel (Core Panel + SLC6A4 add-on) SLC6A4 S/S SLC6A4 THERAPEUTIC IMPLICATIONS (adapted from published resources) Phenotype Poor Responder Decreased serotonin transporter expression expected. Risk of decreased response to SSRIbased therapies and increased risk of adverse events. Consider non-SSRI antidepressant therapies, such as SNRIs or tricyclic antidepressant alternatives. CONFIDENTIAL COPYRIGHT PGXL LABORATORIES 2012 CYP3A4 Phenotype Partially Decreased Metabolizer CYP3A5 Phenotype Decreased Metabolizer CYP1A2 Phenotype Hyperinducer THERAPEUTIC IMPLICATIONS (adapted from published resources) Decreased metabolic clearance expected with increased risk of dose-dependent side effects. Common CYP3A4 medications below. THERAPEUTIC IMPLICATIONS (adapted from published resources) Genotype consistent with reduced CYP3A5 enzymatic activity and represents the majority (60-80%) of the population. For DMs, maintenance dosages for most CYP3A drugs are lower than extensive metabolizers. Common CYP3A5 medications below. THERAPEUTIC IMPLICATIONS (adapted from published resources) Rapid metabolism expected, especially in smokers. Consider dose increases for medications inactivated by CYP1A2 particularly in smokers, or alternative medications not metabolized by CYP1A2. Common CYP1A2 medications below. Patients who are homozygous for the CYP1A2*1F/*1F genotype may exhibit even higher rates of CYP1A2 enzymatic activity and have been described as ultra-rapid metabolizers for olanzapine. As an example, carriers of CY1A2*1F with the hyperinduction phenotype may exhibit as much as 50% lower than expected plasma levels of olanzapine, clozapine, and haloperidol, which could lead to subtherapeutic response. Hyperinducers may require increased dosages of CYP1A2 substrates due to higher than normal rates of drug metabolism in the presence of an inducer. PGXL Psychiatry Panels – Metabolic Routes PSYCHIATRY Antidepressants Antipsychotics, Mood Stabilizers Generic Amitriptyline Bupropion Citalopram Clomipramine Brand Various brands Wellbutrin Celexa Ananfranil Metabolic Route CYP2D6 CYP1A2, (CYP2B6) CYP2C19 CYP2D6, CYP1A2 Desipramine Desvenlafaxine Doxepin Duloxetine Escitalopram Fluoxetine Fluvoxamine Imipramine Norpramin Pristiq Sinequan Cymbalta Lexapro, various Prozac Luvox Tofranil Maprotiline Mianserin Mirtazapine Nefazadone Nortriptyline Ludiomil Various brands Remeron Serzone Pamelor, Aventyl Paroxetine Reboxetine Sertraline Trazadone Trimipramine Venlafaxine Paxil Edronax Zoloft Desyrel Surmontil Effexor CYP2D6 CYP3A4/CYP3A5 CYP2D6 CYP2D6, CYP1A2 CYP2C19 CYP2D6 CYP2D6 CYP2D6, CYP2C19, CYP1A2 CYP2D6 CYP2D6, CYP1A2 CYP2D6, CYP1A2 CYP3A4/CYP3A5 CYP2D6, CYP3A4/CYP3A5 CYP2D6 CYP3A4/CYP3A5 CYP2C19 CYP3A4/CYP3A5 CYP2D6 CYP2D6 Generic Alprazolam Amphetamine Aripiprazole Asenapine Atomoxetine Buspirone Carbamazepine Chlorpromazine Clozapine Diazepam Haloperidol Iloperidine Lurasidone Brand Xanax Adderall Abilify Saphris Strattera Buspar Various brands Thorazine Clozaril Valium Haldol Fanapt Latuda Metabolic Route CYP3A4/CYP3A5 CYP2D6 CYP2D6 CYP1A2 CYP2D6 CYP3A4/CYP3A5 CYP3A4/CYP3A5 CYP2D6 CYP1A2 CYP2C19 CYP2D6 CYP2D6 CYP3A4/CYP3A5 Midazolam Olanzapine Perphenazine Promazine Quetiapine Versed Zyprexa Trilafon Sparine Seroquel CYP3A4/CYP3A5 CYP1A2 CYP2D6 CYP1A2 CYP3A4/CYP3A5 Risperidone Thioridazine Triazolam Ziprasidone Zuclopenthixol Risperidol Mellaril Halcion Geodon Various brands CYP2D6 CYP2D6 CYP3A4/CYP3A5 CYP3A4/CYP3A5 CYP2D6 • PGXL exclusive provider of SULT4A1 marker (schizophrenia, bipolar disorder) – Enhanced efficacy on olanzapine – Reduced risk of hospitalization – Reduced hospitalization costs SULT4A1 • Brain enzyme that interacts with neurochemicals • Efficacy advantage with olanzapine Efficacy Hospitalization SULT4A1 Interpretations Gene THERAPEUTIC IMPLICATIONS (adapted from published resources) SULT4A1-1 Consider olanzapine. SULT4A1-1 positive patients have been shown to demonstrate POSITIVE enhanced treatment efficacy and reduced hospitalization risk when treated with olanzapine compared to both SULT4A1-1 negative patients treated with olanzapine and SULT4A1-1 positive patients treated with risperidone. SULT4A1-1 SULT4A1-1 negative patients treated with olanzapine do not display the expected efficacy NEGATIVE advantage compared to other atypical antipsychotics. Is olanzapine likely to have increased efficacy? Yes See SULT4A1 Does consensus data suggest alternatives to risperidone? Yes See CYP2D6 Are SSRIs likely to have decreased efficacy and increased Yes risk of side effects? See SLC6A4 See below for possible dosage considerations. STA2R Panel Report SULT4A1 rs763120 CC rs5764010 TT SULT4A1-1 THERAPEUTIC IMPLICATIONS (adapted from published resources) Phenotype POSITIVE Consider olanzapine. SULT4A1-1 positive patients have been shown to demonstrate enhanced treatment efficacy and reduced hospitalization risk when treated with olanzapine compared to both SULT4A1-1 negative patients treated with olanzapine and SULT4A1-1 positive patients treated with risperidone. CYP2D6 *4/*4 CYP2D6 Phenotype Poor Metabolizer THERAPEUTIC IMPLICATIONS (adapted from published resources) Avoid Alternative Consideration Adjust Dosage Adjustment Risperidone† Venlafaxine† Amitriptyline† Quetiapine, olanzapine, clozapine Citalopram, sertraline Citalopram, sertraline Aripiprazole† Clomipramine† Doxepin† Haloperidol† Imipramine† Nortriptyline† Zuclopenthixol† 10 mg/day maximum Decrease 50% Decrease 60% Decrease 50% Decrease 70% Decrease 60% Decrease 50%, or flupenthixol, quetiapine, olanzapine, clozapine SLC6A4 S/S SLC6A4 THERAPEUTIC IMPLICATIONS (adapted from published resources) Phenotype Poor Responder Decreased serotonin transporter expression expected. Risk of decreased response to SSRIbased therapies and increased risk of adverse events. Consider non-SSRI antidepressant therapies, such as SNRIs or tricyclic antidepressant alternatives. CYP2C19 *2/*2 CYP2C19 Phenotype THERAPEUTIC IMPLICATIONS (adapted from published resources) Poor Metabolizer Decreased metabolic clearance expected. Adjust Dosage Adjustment Imipramine† Sertraline† Decrease 30% Decrease 50% CYP1A2 *1F/*1F CYP1A2 THERAPEUTIC IMPLICATIONS (adapted from published resources) SLC6A4 S/S Phenotype SLC6A4 THERAPEUTIC IMPLICATIONS (adapted from published resources) HYPERINDUCER Rapid metabolism expected, especially in smokers. Consider dose increases for Phenotype medications inactivated by CYP1A2 particularly in smokers, or decreased alternative medications. Poor Responder Decreased serotonin transporter expression expected. Risk of response to SSRICommon CYP1A2 next based therapies andmedications increased risk ofpage. adverse events. Consider non-SSRI antidepressant *Lack of efficacy duetherapies, to failure tosuch produce active metabolite; risk of adverse events due to as SNRIs or tricyclic†Increased antidepressant alternatives. diminished drug clearance. CYP3A4 Phenotype Partially Decreased Metabolizer CYP3A5 Phenotype Decreased Metabolizer CYP1A2 Phenotype Hyperinducer THERAPEUTIC IMPLICATIONS (adapted from published resources) Decreased metabolic clearance expected with increased risk of dose-dependent side effects. Common CYP3A4 medications below. THERAPEUTIC IMPLICATIONS (adapted from published resources) Genotype consistent with reduced CYP3A5 enzymatic activity and represents the majority (60-80%) of the population. For DMs, maintenance dosages for most CYP3A drugs are lower than extensive metabolizers. Common CYP3A5 medications below. THERAPEUTIC IMPLICATIONS (adapted from published resources) Rapid metabolism expected, especially in smokers. Consider dose increases for medications inactivated by CYP1A2 particularly in smokers, or alternative medications not metabolized by CYP1A2. Common CYP1A2 medications below. Master Drug Lists • Gene-based drug lists in back of report • Recall for additional drugs possibly affected by genotype that were not on 1st page CYP3A4/5 master drug list CYP3A4/CYP3A5 Substrates PSYCHIATRY Benzodiazepines Alprazolam Xanax Midazolam Versed Triazolam Halcion Antipsychotics Quetiapine Seroquel Ziprasidone Geodon Buspirone Buspar Lurasidone Latuda Carbamazepine Various brands Antidepressants Desvenlafaxine Pristiq Vilazodone Viibryd Trazadone Desyrel Nefazadone Serzone Reboxetine Edronax Nortriptyline Pamelor, Aventyl CARDIOLOGY Quinidine Ticareglor Rivaroxaban Statins Atorvastatin Lovastatin Mevastatin Simvastatin Ca Channel Blockers Amlodipine Diltiazem Felodipine Lercanidipine Nifedipine Nisoldipine Nitrendipine Verapamil Various brands Brilinta Xarelto Lipitor Mevacor, Advicor Compactin Zocor, Vytorin, Caduet, Simcor Norvasc Cardizem Plendil Zanidip Adalat Sular Various brands Various brands OTHER Antimicrobials/antivirals Clarithromycin Erythromycin Telithromycin Indinavir Nelfinavir Ritonavir Saquinavir Biaxin E-Mycin Ketek Crixivan Viracept Norvir Fortovase Steroids Estradiol Hydrocortisone Progesterone Testosterone Various brands Various brands Various brands Various brands Chemotherapeutics Vincristine Docetaxel Oncovin Taxotere Pain Management Cyclobenzaprine Fentanyl Alfentanil Flexaril Actiq, Duragesic Alfenta Immunosuppressants Cyclosporine Tacrolimus Gengraf Prograf CYP2D6 Pain Management Codeine** Oxycodone** Hydrocodone** Tramadol** Various brands Oxycontin, various Various brands Ultram, various Cardiology Carvedilol Metoprolol Propanolol Timolol Propafenone Flecainide Coreg Toprol-XL Inderal, various Blocadren Rythmol Tambocor Other Loratadine Donepezil Dextromethorphan Tamoxifen** Claritin Aricept Various brands Various brands Psychiatry Antidepressants Fluoxetine Fluvoxamine Paroxetine Venlafaxine Duloxetine Maprotiline Mirtazapine Amitriptyline Clomipramine Desipramine Doxepin Imipramine Nortriptyline Trimipramine Prozac Luvox Paxil Effexor Cymbalta Ludiomil Remeron Various brands Ananfranil Norpramin Sinequan Tofranil Pamelor, Aventyl Surmontil Antipsychotics Haloperidol Risperidone Aripiprazole Zuclopenthixol Perphenazine Thioridazine Iloperidine Chlorpromazine Atomoxetine Amphetamine Haldol Risperidol Abilify Various brands Trilafon Mellaril Fanapt Thorazine Strattera Adderall Psych Req Form Thank You! 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