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IF:Behavioral Health © 2009 - 2014 PGXL Laboratories Treatment-Resistant Depression Problem and Implications • 23 million Americans take prescription medications for depression • 253 million prescriptions in 2010 • Prescribers have no way of knowing which class of drugs or which dose will work for the patient • 63% of patients fail first-line therapy • 16.3% stop taking medication altogether due to drug intolerance • Trial-and-Error prescribing for depression does not work Continued… Treatment Resistant Depression (TRD) Clinical Facts Economic Implications Ref TRD occurs in 10% to 50% of patients with diagnosis of depression TRD increases medical costs: $6,852 annually verses $13,980 annually 1 TRD patients are 50% more likely to be hospitalized TRD hospitalization increases medical costs: $6,512 annually verses $42,344 annually 2 Patients with depression diagnosis and PGx identified variants have 69% greater health care visits and 4 times greater disability claims Depression diagnosis with PGx identified variants increased medical costs: $5,188 higher than patients with depression diagnosis and no PGx identified variants 3 References 1. Cost implications of treatment resistant depression. Russell et al J Clin Psych 2004;65(3):341-7. 2. Impact of Treatment Resistant Depression on Healthcare costs. Crown et al J Clin Psych 2002;63(11):963-71 3. Retrospective study of healthcare utilization that could have been avoided through PGx. Psychiatric pharmacogenetics predicts health resource utilization of outpatients with anxiety and depression. Transl Psychiatry 2013;3:e242 Property of PGxl Laboratories Biochemical and Physiological Effects of Drugs Pharmacokinetics and Pharmacodynamics Pharmacokinetics What the body does to the drug • Metabolism, bioavailability • Pro-drugs and active drugs • Washing the active agent from the body Distribution Pharmacodynamics What the drug does to the body • Therapeutic, sub-therapeutic, toxic Phenotypes Categories of People With Specific CYP450 Variants (polymorphism) • Effective Metabolizer (EM) - Normal genetics - Two good copies of the genetic code required for metabolism • Intermediate Metabolizer (IM) - Reduced enzymatic activity - One good copy, one bad copy of code required for metabolism - May render the drug a no-go or require dose adjustment Continued… Phenotypes Categories of People With Specific CYP450 Variants (polymorphism) • Poor Metabolizer (PM) - Complete lack of enzymatic activity - Two bad copies of required code - May render the drug a no-go or require dose adjustment • Ultra-rapid Metabolizer (UM) - Higher-than-average enzymatic activity - Three or more copies of required code - May render the drug a no-go or require dose adjustment …Continued Incidence of Variants Are Variants Rare or Common? Gene EM IM PM UM Total CYP2D6 53% 35% 10% 2% 47% CYP2C19 36% 32% 4% 28% 64% CYP2C9 57% 40% 3% NA 43% CYP3A4 87% 12% 1% NA 13% CYP3A5 1% 18% 81% NA 99% SLC6A4 25% 50% 25% NA 75% Cytochrome P450 Phase I Metabolism CYP2D6 CYP2C9 CYP2C19 CYP3A4 CYP3A5 CYP1A2 Pharmacogenetics in TRD Leading Anti-Depression Drugs are Metabolized by Genes in the CYP450 Superfamily • Cytochrome P450 Enzymes - Enzymes bound to membranes within a cell (cyto) - Contain a heme pigment (chrome and P) - Heme pigment absorbes light at a wavelength of 450 nm • More than 50 enzymes in CYP450 - CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5 - 90% of drugs are metabolized by these 6 enzymes Pharmacogenetics in TRD Antidepressants Generic Amitriptyline Bupropion Citalopram Clomipramine Desipramine Desvenlafaxine Doxepin Duloxetine Escitalopram Fluoxetine Fluvoxamine Imipramine Maprotiline Mianserin Mirtazapine Nefazadone Nortriptyline Paroxetine Reboxetine Sertraline Trazadone Trimipramine Venlafaxine Vilazodone Brand Various brands Wellbutrin Celexa Ananfranil Norpramin Pristiq Sinequan Cymbalta Lexapro, various Prozac Luvox Tofranil Ludiomil Various brands Remeron Serzone Pamelor, Aventyl Paxil Edronax Zoloft Desyrel Surmontil Effexor Viibryd Metabolic Route CYP2D6 CYP1A2, (CYP2B6) CYP2C19 CYP2D6, CYP1A2 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 CYP3A4/CYP3A5 Drugs With Consensus Recommendations Gene CYP2D6 Phenotype Intermediate Metabolizer 35% of the population Poor Metabolizer 10% of the population Ultra Rapid Metabolizer 1 to 7 in every 100 people 29% of North African and Ethiopian populations 6% of African American, Caucasian and Greek populations Drug venlafaxine risperidone imipramine zuclopenthixol doxepin venlafaxine risperidone amiptriptyline aripiprazole clomipramine doxepin haloperidol imipramine nortriptyline risperidone zuclopenthixol amiptriptyline clomipramine paroxetine atomoxetine imipramine nortriptyline venlafaxine doxepin haloperidol Consensus Action Avoid Avoid Dose Adjustment Dose Adjustment Dose Adjustment Avoid Avoid Avoid Dose Adjustment Dose Adjustment Dose Adjustment Dose Adjustment Dose Adjustment Dose Adjustment Avoid Avoid Avoid Avoid Avoid Avoid Dose Adjustment Dose Adjustment Dose Adjustment Dose Adjustment Dose Adjustment Drugs With Consensus Recommendations Gene 2C19 SLC6A4 Phenotype Intermediate Metabolizer 32% of the population Poor Metabolizer 4% of the population Ultra Rapid Metabolizer 28% of the population Intermediate Responder Poor Responder Drug imipramine sertaline imipramine sertraline citalopram escitalopram SSRI’s SSRI’s Consensus Action Dose Adjustment Dose Adjustment Dose Adjustment Dose Adjustment Dose Adjustment Dose Adjustment Avoid Avoid Our report will suggest specific actions for these drugs only. IF:Behavioral Health Report We test and report on Kinetics and Dynamics PGXL IF:Behavioral Health The addition of SLC6A4 Promoter SS Version Lower Expression SLC6A4 gene LG Version Lower Expression SSRI Resistant >2-fold risk of failure and ADRs 75% of population are carriers LA Version Higher Expression Greatest SSRI Efficacy >2-fold greater response 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 X EMs Clearance UMs Ramey-Hartung, El-Mallakh, Reynolds. Clin Lab Med 2008;28:627-43. Property of PGxl Laboratories Property of PGxl Laboratories TRD continuum of risk • 50-60% depressed patients have recurrence, up to 63% fail 1st line Rx (SSRIs) – increased # of Rx, hospitalization risk, costs (19x higher) SLC6A4 identifies SSRI resistance/sensitivity Depression Dx 1st Rx SSRI (Variant 25% PR, 50% IR) Dose titration based on response and tolerance CYPs identify dose titration requirements TRD 10-50% Crown et al. J Clin Psych 2002; Russell et al. J Clin Psych 2004; APA Major Depression Treatment Practice Guidelines 2010 Psychosis Clinical Fact Economic Implication Ref Schizophrenic patients have a 38% to 51% probability of readmission following initial hospitalization. Re-hospitalized patients incur twice the medical costs compared to patients not requiring rehospitalization 1 SULT Negative patient taking Olanzapine have 61% relapse vs 11% SULT positive $7,786 no recent relapse verses $38,104 to 73,549 if recent relapse 1 2D6 PM patients taking risperidone have 3.4x risk of ADR and 6x risk of discontinuation. 74% of patients stop taking their prescribed antipsychotic medication at 18 months due to lack of efficacy or ability to tolerate the medication 2D6 PM and UMs have increased risk of ADRs. 1. 2. 3. 4. 5. 2,3, 4 Cost to treat relapse is $38,501. Average length of stay is 7 days longer with risperidone ADR, increased cost $4000-6000 PMs and UMs exhibit 239% higher costs than normal metabolizers. PGX-guided therapy reduced to 28%. Equates to $67,064 reduced to $20,532 with PGx testing 4, 5 Impact of SULT on hospitalization for psychotic disorder. iu et al. Prim Care Comp 2012;14(3). And Ascher et al BMC Psych 2010;10:2. Effectiveness of anti-psychotic drugs in patients with chronic schizophrenia N Eng J Med 2005;353:1209-1223 The cost of relapse and predictors of relapse in the treatment of schizophrenia. BMC Psych 2010;10:2 The CYP2D6 poor metabolizer phenotype may be associated with risperidone adverse drug reactions and discontinuation. J Clin Psychiatry 2005;66(1):15-27. Does pharmacogenetic testing for CYP450 2D6 and 2C19 among patients with diagnoses within schizophrenic spectrum reduce treatment costs? Basic Clin Pharmacol Toxicol 2013 epub; doi:10.1111/bcpt.12093. Property of PGxl Laboratories Pharmacogenetics in Psychosis In Addition to CYP450, We Are Exclusive Providers of SULT4A1-1 • Cytochrome P450 Enzymes - Enzymes bound to membranes within a cell (cyto) - Contain a heme pigment (chrome and P) - Heme pigment absorbes light at a wavelength of 450 nm • More than 50 enzymes in CYP450 - CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5 - 90% of drugs are metabolized by these 6 enzymes • SULT4A1-1 Status Impacts Choice of Olanzapine - Positive SULT4A1 = enhanced treatment efficacy and reduced hospitalization - Positive SULT4A1 demonstrates enhanced treatment efficacy compared to risperidone Pharmacogenetics in Psychosis Antipsychotics, Mood Stabilizers Generic Alprazolam Amphetamine Aripiprazole Asenapine Atomoxetine Buspirone Carbamazepine Chlorpromazine Clozapine Diazepam Haloperidol Iloperidine Lurasidone Midazolam Olanzapine Perphenazine Promazine Quetiapine Risperidone Thioridazine Triazolam Ziprasidone Zuclopenthixol Brand Xanax Adderall Abilify Saphris Strattera Buspar Various brands Thorazine Clozaril Valium Haldol Fanapt Latuda Versed Zyprexa Trilafon Sparine Seroquel Risperdal Mellaril Halcion Geodon Various brands Metabolic Route CYP3A4/CYP3A5 CYP2D6 CYP2D6 CYP1A2 CYP2D6 CYP3A4/CYP3A5 CYP3A4/CYP3A5 CYP2D6 CYP1A2 CYP2C19 CYP2D6 CYP2D6 CYP3A4/CYP3A5 CYP3A4/CYP3A5 CYP1A2 CYP2D6 CYP1A2 CYP3A4/CYP3A5 CYP2D6 CYP2D6 CYP3A4/CYP3A5 CYP3A4/CYP3A5 CYP2D6 Incidence of Variants in the Population Are Variants Rare or Common? Gene EM IM PM UM Total CYP2D6 53% 35% 10% 2% 47% CYP2C19 36% 32% 4% 28% 64% CYP2C9 57% 40% 3% NA 43% CYP3A4 87% 12% 1% NA 13% CYP3A5 1% 18% 81% NA 99% SLC6A4 25% 50% 25% NA 75% Caucasians African Americans Asians Positive 23% 3% 45% Negative 77% 97% 55% SULT4A1-1 IF:Behavioral Health Report We test and report on Kinetics and Dynamics Gene THERPEUTIC IMPLICATIONS (adapted from published resources) SULT4A1-1 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. SULT4A1-1 NEGATIVE SULT4A1-1 negative patients treated with olanzapine do not display the expected efficacy advantage compared to other atypical antipsychotics. Catechol-O-Methyltransferase (COMT) Degrades dopamine and norepinephrine, primarily in the prefrontal cortex of the brain COMT Phenotype THERAPEUTIC IMPLICATIONS (adapted from published resources) High Activity The COMT Val/Val genotype results in increased COMT activity and decreased dopamine levels in the prefrontal cortex. Compared to patients with the Met allele, Val/Val patients with depression are less likely to achieve remission when treated with SSRI antidepressants, and Val/Val patients with schizophrenia are less likely to demonstrate improved cognitive effects when treated with antipsychotics. Val/Val patients may benefit from agents that increase dopamine availability including methylphenidate and amphetamine. Intermediate Activity The COMT Val/Met genotype results in average COMT activity and dopamine levels, and patients with this genotype are more likely to respond to psychotropic medications than those with the Val/Val genotype. Low Activity The COMT Met/Met genotype results in decreased COMT activity and increased dopamine levels in the prefrontal cortex. Compared to Val/Val, Met/Met patients with depression are more likely to achieve remission when treated with SSRI antidepressants, and Met/Met patients with schizophrenia are more likely to demonstrate improved cognitive effects when treated with antipsychotics. Met/Met patients have an increased risk of adverse effects when treated with methylphenidate or amphetamine and should be considered for non-stimulant alternatives.
