Pharmacogenomics and Customized Therapies in Psychiatry

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1 Pharmacogenomics and Customized Therapies in Psychiatry Toshiyuki Someya,, MD, PhD Department of Psychiatry Niigata University Graduate School of Medical and Dental Sciences The efficacy and side effects of psychotropic drugs are highly variable across patients and between human populations. A significant portion of this variation is likely due to individual genetic differences -- both in pharmacokinetic & pharmacodynamic pathways. Customized therapies and the role of genetics on interindividual and interethnic differences in drug response represent an area of growing interest.

2 Initial studies in the field focused on single genes concerning primarily drug metabolism. Increasingly, genetic variability of molecular drug targets and their relevance for psychotropic drug efficacy and safety are being studied. Personalized Medicine The Concept of Drug-Predictive Test Combination Patients with same diagnosis Non-responders 1 and toxic responders Responders and patients not predisposed to toxicity 2 Treat with alternative drug or dose Treat with conventional drug or dose

3 Comprehensive pharmacogenomic study of psychotropic-induced induced adverse effects Antipsychotics-induced adverse effects Weight gain/obesity Glucose intolerance Hyperprolactinemia Abnormal ECG Malignant syndrome Dyskinesia Dystonia Antidepressants-induced adverse effects Digestive symptom Genetic factors: Site of action, Drug metabolism Gender difference Age Life environment Physical illness Establishment of tailor-made pharmacotherapy Health and Labour Sciences Reseach Grants (Research on Psychiatric and Neurological Diseases and Mental Health) Prediction of Clinical Effects and Side Effects of Psychotropics using Genome Information (24~28) Development of Personalized Therapy for Schizophrenia and Mood disorder by Utilizing Genomic Medicine Chief Toshiyuki Someya (Niigata University) Collaborators Sunao Kaneko (Hirosaki University) Norio Ozaki (Nagoya University) Mitsuhiko Yamada (National Center of Neurology and Psychiatry)

4 Relation between Plasma Nortriptyline Levels and Clinical Response Plasma nortriptyline concentration(μg/l) Patients Responders Non-Responders Recommended therapeutic range (Montgomery SA et al, Br Med J 1977) Evidence Suggesting the Existence of Upper Therapeutic End of Plasma Levels for Antidepressants Drug Upper End Clinical Consequence Nortriptyline >15 ng/ml HDRS amelioration score decreases Cardiac conduction delay Imipramine + desipramine >25 ng/ml Response rate is no better than < 125 ng/ml Cardiac conduction delay Increased diastolic blood pressure Amitriptyline + nortriptyline >35 ng/ml >45 ng/ml >1 ng/ml Abnormal EEG changes Increased risk of delirium Coma and/or seizures

5 However, for the newer antidepressants such as the selective serotonin reuptake inhibitors (SSRIs( SSRIs), Therapeutic Drug Monitoring (TDM) and concentration-effect effect relationships have not been uniformly consistent. This does not necessarily indicate that pharmacokinetic factors are not important for response to SSRIs -- but rather, drug concentrations in the blood are unlikely to singularly account for a major portion of variability in SSRI response. Additionally, it is noteworthy that clinical significance of pharmacokinetic variability can be unmasked or discerned more effectively upon joint investigation of genetic or biological variability in molecular targets. Fluvoxamine Study

6 Relationship between Plasma Concentration of Fluvoxamine and Clinical Response (PK-PD PD study) Subjects Entry; 122 depressed outpatients (HAM-D-17 score 14) Stepwise multi fixed-dose design by Fluvoxamine 25 ~ 2 mg/d 12-week; 8 dose tolerant patients Receiver Operating Characteristics (ROC) curve analysis Dose tolerant patients Age (y) 4.3 (14.8) a Gender (male/female) 44 / 36 Baseline HAMD-17 score 2.5 (5.5) a Remitters 39 a Values are given as means (SD).

7 Remission and Non-remission in the Stepwise Fixed-Dose (Initial HAM-D-17 score 2 ) Daily FLV dose Remission (ROC case) Non-remission (ROC case) 25 mg 1 (1) 5 (29) 5 mg 3 (3) 47 (37) 1 mg 6 (6) 41 (37) 15 mg 6 (6) 35 (32) 2 mg 5 (5) 3 (27) Total 21 (21) 23 (162) 1.8 Cumulative remission rate.6.4 Fig. 1. ROC curve showing relationship between remission, non-remission and FLV plasma concentration in HAM-D-17 score 2 group ng/ml (p<.1, χ2 analysis; power=96%) Cumulative non-remission rate (Suzuki et al. J Clin Psychopharmacology, in press)

8 Remission and Non-remission in the Stepwise Fixed-Dose (Initial HAM-D-17 score 2 ) Daily FLV dose Remission (ROC case) Non-remission (ROC case) 25 mg 1 (1) 5 (29) 5 mg 3 (3) 47 (37) 1 mg 6 (6) 41 (37) 15 mg 6 (6) 35 (32) 2 mg 5 (5) 3 (27) Total 21 (21) 23 (162) 1 mg/d FLV group 15 mg/d FLV group Cumulative remission rate Cumulative remission rate ng/ml 79.9 ng/ml Cumulative non-remission rate Cumulative non-remission rate

9 Interindividual Variation of Plasma Concentration of Fluvoxamine (PK study) Plasma concentration of fluvoxamine (ng/ml) Relationship between Daily Dose of Fluvoxamine and Steady-state Plasma Concentration of Fluvoxamine Dose of fluvoxamine (mg/day) (Suzuki et al, submitted)

10 F3C C CH2 CH2 CH2 CH2 O CH3 N O CH2 CH2 NH2 AO Fluvoxamine F3C C CH2 CH2 CH2 CH2 O CH3 N O CH2 COOH deaminated metabolite F3C C CH2 CH2 CH2 CH2 O CH3 N OH side chain cleaved metabolite CYP2D6, CYP1A2 NAT F3C F3C C N O CH2 CH2 CH2 COOH CH2 CH2 AO NH2 O-demethylated metabolite C CH2 CH2 CH2 COOH N O CH2 COOH deaminated and O-demetylatedO metabolite F3C C CH2 CH2 CH2 CH2 O CH3 N O CH2 CH2 NH CO CH3 acetylated metabolite Metabolism of fluvoxamine and enzymes suggested to catalyze the Phase I reactions:cyp isoenzymes, amine oxidase(ao), and N-acetyltransferase(NAT).. (C.Hiemcke,S.Hartter/Pharmacology &Therapeutics 85(2)11-28) Effect of CYP2D6 on the Metabolism of Fluvoxamine (PK predictive test)

11 Spigset O, et al. (Eur( J Clin Pharmacol 1997) Plasma concentrations of fluvoxamine was signigicantly higher in poor metabolizers of dextromethorphan than in extensive metabolizers,, in a study of receiving a single oral dose of 5 mg fluvoxamine. Carrillo JA, et al. (Clin( Pharmacol Ther 1996) Poor metabolizers of debrisoquin had significantly low clearance of fluvoxamine, in another study of receiving a single oral dose of 5 mg fluvoxamine. Ohara K, et al. (Eur( J Clin Pharmacol 23) Plasma concentrations of fluvoxamine divided by daily dose of fluvoxamine per body weight were not affected by CYP2D6*1 genotypes. Daily doses of fluvoxamine ranged from 25 mg/day to 15 mg/day. Gerstenberg G, et al. (Ther Drug Monit 23) There was no significant difference among the patients with no (*1/*1), one (*1/*5 and *1/*1), and two (*5/*1 and *1/*1) mutated alleles in the steady-state state plasma concentrations of fluvoxamine corrected to the mean body weight. Daily doses of fluvoxamine was 2 mg/day. Subjects 87 Japanese inpatients or outpatients treated with fluvoxamine 2 age 65 years old Exclusion: with obvious physical illness smokers ( 2 cigarettes/day) treated with other drugs except benzodiazepines Blood sampling Maintained on the same daily doses of fluvoxamine for at least 2 weeks to obtain steady-state concentrations of fluvoxamine Blood sampling was done 12 hours after the last dosage

12 Genotyping CYP2D6*5 and *1: identified by the polymerase chain reaction (PCR) method The patients are divided into three groups by the number of mutated alleles: mutated allele (*1 / *1) 1 mutated allele (*1 / *5, *1 / *1) 2 mutated alleles (*5 / *1, *1 / *1) Statistical analysis Comparisons were made among genotype groups by Kruskal Wallis analysis at fluvoxamine doses of 25, 5, 1, 15 and 2 mg/day The level of statistical significance: P <.5 Effect of the CYP2D6 on the Plasma Concentration of Fluvoxamine Plasma concentration of fluvoxamine (ng/ml) Figure 2-a. at 25 mg/day P =.12 P = Figure 2-b. at 5 mg/day P =.2 P = Number of mutated alleles of CYP2D6 Bars represent median

13 Effect of the CYP2D6 on the Plasma Concentration of Fluvoxamine Plasma concentration of fluvoxamine (ng/ml) Figure 2-c. at 1 mg/day P = Figure 2-d. at 15 mg/day Number of mutated alleles of CYP2D6 Bars represent median Multidrug resistant transporter (MDR1, ABCB1) The MDR1 is expressed in normal tissues such as liver, kidney, and intestine where it contributes to the elimination of xenobiotics and drugs into bile and urine or limits drug absorption from the gastrointestinal tract. It has been shown that polymorphism C3435T in MDR1 can alter p-glycoprotein conformation and protein activity/substrate specificity (Kimchi-Sarfaty C et al. Science 27). However, there have been few clinical studies investigating effects of the functional status of MDR1 on pharmacokinetics of antidepressants.

14 The structure of MDR1 and location of gene polymorphisms (Sakaeda T. 25) Relationship between MDR1 C3435T genotype and steady-state state plasma concentration of fluvoxamine in the 2 mg/day group P =.19 (Kruskal-Wallis test) 4 P =.31 (Mann-Whitney test) Fluvoxamine level (ng/ml/mg) CC CT TT MDR1 C3435T (Fukui et al. Ther Drug Monit 27)

15 Conclusions CYP2D6 may affect the disposition of fluvoxamine more greatly at lower doses of fluvoxamine but less at higher doses of fluvoxamine. On the contrary, MDR1 had a significant effect on plasma fluvoxamine concentration only at the higher dose of fluvoxamine, likely because of CYP2D6 saturated at these higher doses. This is important because this means that pharmacogenetic association studies may need to consider stratification of study samples by dose as well. Moreover, the degree of genetic contribution may vary with dose genetic contributions need not be uniformly constant across all psychotropic drug doses. Relationship between Clinical Response and Serotonin 1A Receptor Polymorphism (PD predictive test)

16 Effect of the 5HT1A Receptor Genotypes on Treatment Response to Fluvoxamine (%) Reduction in the HAMD-17 scores ** **:P<.1 *:P<.5 * Gly/Gly Gly/Asp Asp/Asp * Schematic model of brain 5-HT system Week Polymorphisms of the 5-5 HT1A receptor gene (Suzuki et al. Pharmacogenomics J 24) Relationship between Side Effects and Polymorphisms in the Serotonin 2A Receptor and CYP2D6 Genes (PD predictive test)

17 Detected alleles by PCR 1 A-1438G of 5-HT2A receptor 2 C195T and Pro16Ser of 5-HT3A receptor 3 Tyr129Ser of 5-HT3B receptor 4 *5 and *1 allele of CYP2D6 5-HT receptors are thought to be associated with the gastrointestinal side effects induced by SSRIs. CYP2D6 may also be associated with the side effects induced by fluvoxamine, since the plasma fluvoxamine concentration depends on a CYP2D6 gene polymorphism. Subject 1 patients with depression, who gave the written informed consent Diagnoses M : F 47 : 53 Initial HAMD Score (17item) 2.8 ± 5.1 Major Depressive Disorder n = 85 Adjustment Disorder with D. 7 Depressive Disorder NOS 4 Others 4

18 Effect of the A-1438G A polymorphism of the 5-HT2A 5 receptor gene on gastrointestinal side effects induced by fluvoxamine Cumulative Incidence of Gastrointestinal Side Effects G/G A/G A/A 4 HR 2.895, p<.1 HR 2.214, p< Week 12 Polymorphisms of the 5-HT2A 5 receptor gene (Suzuki et al. Neuropsychopharmacology 26) Effect of the CYP2D6 genotype Combination effect of the 5-HT2A 5 receptor and the CYP2D6 gene polymorphism Cumulative Incidence of Gastrointestinal Side Effects HR=1.82, p< Lower Metabolizers (LMs).6.5 Normal Metabolizers (NMs) Week HR=4.24, p< Week LMs with G/G NMs with G/G NMs with A/A 1 12 (Suzuki et al. Neuropsychopharmacology 26)

19 Conclusion There were six LMs of CYP2D6 who had the G/G genotype of the 5-HT2A receptor gene, and all of them suffered from gastrointestinal side effects. Among 11 LMs of CYP2D6 who had the A/G genotype, nine (81.8%) suffered from gastrointestinal side effects. In clinical situations, taking account of these results, tailormade pharmacotherapy for fluvoxamine based on genetic factors may be possible. Paroxetine Study

20 Relationship between Side Effects and Polymorphisms in the Serotonin 3A and 3B Receptor Genes (PD predictive test) Subjects Seventy-eight Japanese psychiatric patients, who gave the written informed consent were included in this study. M : F 28:5 Age 38.4±13.8(range 18~7 years) Diagnoses Major depressive disorder 39 Anxiety disorder 25 Adjustment disorder 6 Depressive disorder NOS 7 Other mood disorder 1

21 Study design The patients visited the hospital every 2 weeks and side effects, including nausea, were assessed at each visit. The paroxetine dose was increased from 1 or 2 mg/day to 3 and 4 mg/day in response to clinical symptoms. We rated the side effects during the last 2 weeks and evaluated the severity of nausea according to our original scale which included five graded items. Subjects with a score of or 1 were defined as subjects without nausea, and those with a score or 2, 3 or 4 were defined as having nausea. Genotyping Polymerase chain reaction was used to determine 1 C195T and Pro16Ser polymorphisms of HTR3A (Niesler et al, 21) 2-1_-12AAG Ins/Del and Tyr129Ser polymorphism of HTR3B (Tremblay et al, 23) 3 CYP2D6*1, *2, *5 and *1 alleles (Johansson et al, 1994 and Steen et al, 1995)

22 Polymorphisms of HTR3B G>A Ala154Ala AAG deletion -1_-12 A>C Tyr129Ser CA deletion 27721_27722 G>A Ala223Thr G>A -3 C>T G>A A>G A>T C>T G>A T>A Chromosome 11q 23.1 Relationship between the HTR3B gene polymorphism and nausea HTR3B Tyr129Ser Tyr/Tyr Tyr/Ser Ser/Ser Tyr/Ser + Ser/Ser Sex ( M/F ) 16/19 1/26 2/5 12/31 P Age ±SD P Nausea + (n=15) (%) ( 73.3 ) ( 26.7 ) (. ) ( 26.7 ) Nausea - (n=63) (%) ( 38.1 ) ( 5.1 ) ( 11.8 ) ( 61.9 ) P.38 *.14 * Sugai et al.: The Pharmacogenomics Journal, 26

23 Logistic regression analysis of independent variables to nausea Independent variable Partial regression coefficients P Odd ratio (95% confidence interval) Sex ( ) Age ( ) Daily dose of Paroxetine ( ) HTR3B Tyr129Ser genotype ( ) Sugai et al.: The Pharmacogenomics Journal, 26 Relationship between the HTR3A gene polymorphisms and nausea HTR3A Pro16Ser HTR3A C195T Pro/Pro Pro/Ser Ser/Ser C/C C/T T/T Sex ( M/F ) 23/34 5/13 /3 15/22 11/16 1/9 P Age ±SD P Nausea + (n=15) (%) ( 8. ) ( 2. ) (. ) ( 6. ) ( 33.3 ) (.7) Nausea - (n=63) (%) ( 71.4) ( 23.8 ) ( 4.8 ) ( 44.4 ) ( 34.9 ) ( 14.3 ) P Sugai et al.: The Pharmacogenomics Journal, 26

24 Relationship between the CYP2D6 gene polymorphism and nausea CYP2D6 *1/*1 *1/*5, *1/*1 *5/*1, *1/*1 Sex ( M/F ) 17/34 5/7 6/9 P.87 Age ±SD P Nausea + (n=15) (%) (17.6) (16.7) ( 26.7 ) Nausea - (n=63) (%) ( 82.4 ) ( 83.3 ) ( 73.3 ) P.716 Sugai et al.: The Pharmacogenomics Journal, 26 H N CH2 O O O CYP2D6 H N CH2 O OH OH F H N Paroxetine CH2 OH O O CH3 H N COMT CH2 O CH3 O OH F Unstable intermediate H N? CH2 OH F Metabolite II F Metabolite I F Metabolite III glucuronide glucuronide and sulfate glucuronide Metabolism of paroxetine and enzymes suggested to catalyze the Phase I reactions: CYP2D6 and catechol-o-methyltransferase(comt).. (C.Hiemcke,S.Hartter/Pharmacology &Therapeutics 85(2)11-28)

25 Relationship between daily dosage of PRX and steady-state state plasma concentration Plasma Paroxetine Level (ng/ml) Dose (mg/day) (Sawamura et al, Eur J Clin Pharmacol 24) Relationship between CYP2D6 genotype and steady-state state plasma concentration of paroxetine in the 1 mg/day group. Plasma Paroetine Level (ng/ml) P<.1 P<.1 *1/*1 *1/*1 *1/*1 *1/*5,*5/*1 CYP2D6 genotype (Sawamura et al, Eur J Clin Pharmacol 24)

26 Clinical Pshychopharmacology Research in Our Group Antipsychotics Antidepressants Pharmacokinetics (PK) # of papers Interindividual variability 9 haloperidol 4,9), timiperone 25), bromperidol 44) amitriptyline 12), clomipramine 13), nortriptyline 43), desipramine 47), paroxetine 83) Metabolic pathway/ Enzyme 2 bromperidol 8,42) Drug interaction 5 haloperidol 29,32,58) fluvoxamine 68,86) Development of TDM kit 2 sultopride 55), haloperidol & bromperidol 79) Pharmacodynamics (PD) 4 bromperidol 44), olanzapine 17) amitriptyline 19), fluvoxamine 138) PK Predictive Test CYP2D6 1 haloperidol 39,58,72) clomipramine 6), amitriptyline 64), nortriptyline 43), desipramine 47), paroxetine 83) CYP2C19 2 clomipramine 6), amitriptyline 64), fluvoxamine 68,86) CYP1A2 1 haloperidol 61) ABCB1 (MDR1) 1 fluvoxamine 116) PD Predictive Test 3 fluvoxamine 77,95), paroxetine 13) Pharmacotherpy based on Pharmacogenetics & TDM Diagnosis (DSM-IV-TR) Pharmacodynamic Predictive Test 5-HTTLPR(S allele, L allele) 5-HT1A(Gly272Asp, -119C/T) 5-HT2A(-1438A/G, 12T/C) 5-HT3B(Tyr129Ser) Pharmacokinetic Predictive Test CYP2D6 genotype CYP2C19 genotype CYP1A2 genotype ABCB1(MDR1) genotype (C3435T) Prediction of Drug Efficacy Prediction of Adverse Drug Reaction Treatment Decisions (to prescribe the right drug, at the right dose, for the right patient) Therapeutic Drug Monitoring (clinical effect, side effect, plasma drug concentration) Ono S, Suzuki Y, Someya T. Japanese Journal of Psychiatric Treatment, 28