Outline. Disclosures. Review of Metabolism. Central Dogma of Genetics. Introduction

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Domenic Shelton
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Outline Psychiatric Pharmacogenomics: Applications in Nursing Personalized Health Care Phases of

Study # 2 Case study # 3 Questions/Discussion Post test Disclosures Review of Metabolism Speakers

and psychiatric diagnoses/symptoms Impact of entire medication regimen on person's experience of

of medication experience, plotted on graphs according to substrate DNA Central Dogma of Genetics DNA

function Transcription RNA Translation Protein Appointments are typically about 45min to 1.

1 Outline Psychiatric Pharmacogenomics: Applications in Nursing Personalized Health Care Phases of metabolism Function of specific genes Case Study # 1 live patient report of her experience Case Study # 2 Case study # 3 Questions/Discussion Post test Disclosures Review of Metabolism Speakers Bureau: Assurex Health Introduction APRN Private practice focused on integrated approach: Medical and psychiatric diagnoses/symptoms Impact of entire medication regimen on person's experience of self Individual responses to medications Before gene testing, paid attention to individual's reports of medication experience, plotted on graphs according to substrate DNA Central Dogma of Genetics DNA creates RNA, which creates proteins DNA changes can have profound effects on protein production and function Transcription RNA Translation Protein Appointments are typically about 45min to 1.5 hours for initial gene test interpretation and recommendations Follow ups are 45 min and then 30 min per patient preference 1

CYP2D6 Alleles *1 Normal wild type CYP2D6 Gene DNA Cytochrome P450

CYP2D6 enzyme Isoform Allele CYP2D6 Expression & Phenotype

*4/*6 Normal *1/*6 Intermediate CYP2B6 alleles *1 normal activity

Increased *4/*6 Normal *1/*6 Intermediate *6/*6 Decreased How

Pharmacogenomic Approach 7% 14% 23% 56% CYP2D6 Phenotype

2 CYP2D6 Alleles *1 Normal wild type CYP2D6 Gene DNA Cytochrome P450 Nomenclature CYP2D6*4 mrna Superfamily Family Subfamily Functional CYP2D6 enzyme Isoform Allele CYP2D6 Expression & Phenotype Implications for Family History Extensive Metabolizer Phenotype *4/*6 Normal *1/*6 Intermediate CYP2B6 alleles *1 normal activity *6 reduced activity *4 increased activity *1/*1 Genotype *1/*4 Increased *4/*6 Normal *1/*6 Intermediate *6/*6 Decreased How Genetics Can Affect Medication Blood Levels Combinatorial Pharmacogenomic Approach 7% 14% 23% 56% CYP2D6 Phenotype Frequency* *Phenotype frequency is based on internal Assurex Health data of over 100,000 tested patients. 2

3 Drug Interactions Poor/null CYP2D6 Male, 80+ years Medications: timoptic eye gtts, simsvastatin, lopressor, Lexapro Presents with sinus congestion, cough Prescribed Claritin D (blood pressure medication interaction) 3 days later: patient acting zombie like, almost non verbal Patient 47 year old Female Caucasian Diagnosis Major depression Additional Information Chronic pain Rheumatoid arthritis Crohn s Disease Asthma Chronic pain: severe joint pain Medication use issues Drug Interactions Normal CYP2D6 Female, 30+ years Medications: Prozac, vitamins, Oxycodone Patient complains of unrelieved pain level 8 Instructed to take Colace with sennekot (cautioned regarding constipation with pain medication) Patient complaining about frequent loose stools Psychiatric Symptoms Depressed Poor sleep Sad Headaches Marital conflict Work difficulty Medications February 2010 duloxetine (Cymbalta ) 120mg venlafaxine (Effexor ) XR 300mg trazodone (Desyrel ) 300mg HS eszopiclone (Lunesta ) 3mg HS fentanyl patch 25mcgs sulfasalazine (Azulfidine ) 1qm BID montelukast (Singulair ) folic Acid methotrexate 25mg IM qwk adalimumab (Humira ) 40mg s.c. q 14 days prednisone Previous Multiple SSRIs TCAs (for sleep) aripiprazole (Abilify ): caused akathisia Drug Interactions Ultrarapid CYP2D6 Male, 40+ years Medications: OxyContin 30mg every 12 hours, Oxycodone 15mg every 4 hours as needed Construction worker with severe neck and back pain Prescribed tramadol, Motrin 800mg four times/24 hours and gabapentin Suspected of drug seeking behavior (rapidly tapered off opioids) Still experiences severe pain for intervals between pain medications Pharmacogenomics Results Assessment CYP2D6: Poor Metabolizer CYP1A2: Ultrarapid Metabolizer CYP2C19: Increased activity on one allele (*1/*41) SLC6A4: Intermediate Response MTHFR: Intermediate Activity 3

(Cymbalta ), venlafaxine (Effexor ), and

150mg Psychiatric Changes After Improved

needs Provide attention and care for son

4 Pharmacogenomics Guided Treatment February 2010 Eliminated duloxetine (Cymbalta ), venlafaxine (Effexor ), and trazodone (Desyrel ) June 2016 Added L methylfolate, escitalopram (Lexpro ) 20mg, desvenlafaxine (Pristiq ) 50mg to 150mg Psychiatric Changes After Pharmacogenomics Guided Treatment Improved mood Enjoys work Able to advocate for needs Provide attention and care for son Sleeps better (disrupted due to pain) 4

Patient #2 Pharmacogenomics Results Patient 34 year old Female Caucasian Diagnosis Depression Anxiety Additional Information Immunodeficiency disorder (CVID) Seizure disorder Hypothyroidism Asthma

doses may be required. [2]: Serum level may be too low, higher doses may be required. [3]: Difficult to predict dose adjustments due to conflicting variations in metabolism.

5 Patient #2 Pharmacogenomics Results Patient 34 year old Female Caucasian Diagnosis Depression Anxiety Additional Information Immunodeficiency disorder (CVID) Seizure disorder Hypothyroidism Asthma Chronic pain (severe) Meningitis Herniated discs Micturition/defecation syncope Pelvic floor dysfunction Orthostatic hypotension Smoker (2 packs per week) [1]: Serum level may be too high, lower doses may be required. [2]: Serum level may be too low, higher doses may be required. [3]: Difficult to predict dose adjustments due to conflicting variations in metabolism. [4]: Genotype may impact drug mechanism of action and result in reduced efficacy. [8]: FDA label identifies a potential gene-drug interaction for this medication. Patient #2 Pharmacogenomics Results Psychiatric Symptoms Severely anxious about having her pain medications taken away Panic attacks around pain medications Depressed but moderate Medications Albuterol 0.083% inhale solution Antibiotic diazepam (Valium ) 5mg and 2mg escitalopram (Lexapro ) 10mg fenofibrate (Tricor ) 160mg Ibuprofen IgG (Privigen ) 10% IVIG 25 grams levothyroxine 25 MCG morphine sulf ER 15mg oxycodone HCL15mg ProAir HFA Inhaler promethazine 50mg Seasonique Senekot Colace tizanidine HCL (Zanaflex ) 4mg Vitamin D 1.25mg Previous Added not subtracted [1]: Serum level of the active compound may be too high, lower doses may be required. [2]: Serum level of the active compound may be too low, higher doses may be required. [4]: Genotype may impact drug mechanism of action and result in reduced efficacy. [7]: Serum level may be too low in smokers. Pharmacogenomics Results Assessment CYP2D6: Intermediate Metabolizer CYP2C19: Intermediate Metabolizer CYP1A2: Ultrarapid Metabolizer SLC6A4: Intermediate Response Valium (2mg, 5mg) minor CYP2C19 substrate Lexapro (10mg) CYP2C19 substrate Tricor (160mg) weak inhibitor CYP2C19 CYP2C19 gene is intermediate function Suggestions Decrease valium dosing due to Tricor inhibitory (even though minor) effect on Valium and on Lexapro No increase in Lexapro Leuothyroxin (25 mcg) Do you separate from food intake and all other meds by at least 1 hour? 5

6 Morphine (15mg): OPR1 substrate Oxycodone (30mg) weak substrate CYP2D6, OPRM1 substrate Promethazine (50mg) CYP2D6 substrate Tizanidine (4mg) CYP1A2 CYP1A2 is overactive breakdown this medication rapidly. Suggest choose alternate OPRM1 gene has reduced function Suggestion Lowest possible analgesic dose as blood levels may be higher than safe CYP2D6 intermediate (reduced) function Suggestion: Eliminate promethazine which can dangerously potentiate action of valium, oxycodone, morphine, and tizanidine Pharmacogenomics Guided Treatment Developed a strategy for tapering medications As of August 2016 eliminated promethazine, tizanidine (Zanaflex ), fenofibrate (Tricor ), and tolterodine (Detrol ) Reduced diazepam (Valium ) and oxycodone levothyroxine separated from food and other medications MS Contin changed to Oxycontin Syncope followed by seizure: Valium Promethazine Tizanidine Valium Oxycodone Morphine S. Promethazine Can lower seizure threshold Can lower blood pressure Increased risk of syncope, head injury Psychiatric Changes After Pharmacogenomics Guided Treatment Anxiety and depression markedly decreased Decrease in syncopal episodes No seizures Decreased fatigue Improved cognition and motor activity Micturition and bowel function have returned to normal Wow, this really proves that everything we ve been saying to so many doctors is true. We re not crazy! Syncope followed by seizure: Albuterol Escitalopram Oxycodone Tizanidine Promethazine Can cause heart rhythm irregularities, prolonged QTC interval, syncope Can cause difficulty with urination and constipation due to drying (anticholinergic) effect Patient 35 years old Female Caucasian Diagnosis Major depressive disorder Generalized anxiety disorder Additional Information Esophageal strictures Suspect for lupus Alcohol use (DUI) Occasional cigarettes 6

7 Psychiatric Symptoms Depressed mood Increased irritability Poor sleep Anxiety: escalate to panic Medications At time of testing topiramate (Topamax ) 200mg HS alprazolam (Xanax ) 0.25mg zolpidem (Ambien ) 10mg HS escitalopram (Lexapro ) 10mg Previous Long history of medications desvenlafaxine (Pristiq ): serotonin syndrome Psychiatric Changes After Pharmacogenomics Guided Treatment Moods are more stable Alcohol consumption reduced Pharmacogenomics Results Assessment CYP2D6: *1 normal/*2a increased CYP2C19: *1 normal/*17 increased CYP1A2: Ultrarapid Metabolizer Pharmacogenomics Guided Treatment Eliminated topiramate (Topamax ) Started (Wellbutrin ) IR 75m BID and (Lamictal ) Kept escitalopram (Lexapro ) 5mg BID Changed alprazolam (Xanax ) and zolpidem (Ambien ) to prn 7

Psychiatric Pharmacogenomics: Introduction and Applications

Psychiatric Pharmacogenomics: Introduction and Applications Moises Gaviria, MD Distinguished Professor of Psychiatry University of Illinois at Chicago Medical Director The Institute of Neurobehavioral