2-1-2016 Role of Pharmacogenetics in Improving the Safety of Psychiatric Care by Predicting the Potential Risks of Mania in CYP 2 D 6 Poor Metabolizers Diagnosed With Bipolar Disorder

One of the main concerns in psychiatric care is safety related to drug management. Pharmacogenetics provides an important tool to assess causes that may have contributed the adverse events during psychiatric therapy. This study illustrates the potential of pharmacogenetics to identify those patients for which pharmacogeneticguided therapy could be appropriate. It aimed to investigate CYP2D6 genotype in our psychiatric population to assess the value of introducing pharmacogenetics as a primary improvement for predicting side effects. A broad series of 224 psychiatric patients comprising psychotic disorders, depressive disturbances, bipolar disorders, and anxiety disorders was included. The patients were genotyped with the AmpliChip CYP450 Test to analyzing 33 allelic variants of the CYP2D6 gene. All bipolar patients with poor metabolizer status showed maniac switching when CYP2D6 substrates such as selective serotonin reuptake inhibitors were prescribed. No specific patterns were identified for adverse events for other disorders. We propose to utilize pharmacogenetic testing as an intervention to aid in the identification of patients who are at risk of developing affective switching in bipolar disorder treated with selective serotonin reuptake inhibitors, CYP2D6 substrates, and inhibitors. (Medicine 95(6):e2473) Abbreviations: BPD = bipolar disorders, BPI = bipolar disorder type I, CGI = clinical global impression, CPIC = Clinical Pharmacogenetics Implementation Consortium, EM = extensive metabolizer, IM = intermediate metabolizer, PM = poor metabolizer, SSRI = selective serotonin reuptake inhibitor, UM = ultrarapid metabolizer. INTRODUCTION T he use of pharmacogenetics in psychiatry is increasingly implemented into clinical practice although there is still limited information supporting their use. Pharmacogenetic tests are available for the practice of psychiatry to gather genetic information aimed at personalized medicine. Approximately, 25% of currently used drugs are metabolized by CYP2D6. To date over 100 allelic variants have been defined for CYP2D6, (http://www.cypalleles.ki.se/). Updated allele frequencies can be found in the Clinical Pharmacogenetics implementation Consortium (CPIC) guidelines. Extensive metabolizers (EMs) are patients with at least 1 fully functional allele. Ultrarapid metabolizers (UMs) show increased metabolic activity. The term intermediate metabolizer (IM) refers to individuals with 1 reduced activity allele and 1 null allele. Patients with reduced activity may be at greater risk of adverse events or may bioactivate prodrugs in a less efficient way. Finally, poor metabolizers (PMs) with 2 nonfunctional alleles are more likely to experience dose-related adverse drug reactions compared to EM patients. Currently, used antidepressant drugs such as paroxetine or fluoxetine are potent inhibitors of CYP2D6 and their use may alter a patient’s phenotype from EM to PM in a process called pheno-copying what constitute an added problem since multiple drugs could have a potential inhibitory effect on CYP2D6. Our study aimed to investigate CYP2D6 genotype in our psychiatric population to assess the value of introducing pharmacogenetics as a primary improvement for predicting side effects. MATERIAL AND METHODS Study Population A total of 224 patients diagnosed with psychotic disorders, depressive disturbances, bipolar disorders (BPD), and anxiety disorders were included. Patients started a medium-term treatment (12–24 months) with antidepressants or antipsychotics while hospitalized in a short-term unit (54%), and patients on an outpatient regime (mental health unit) who started pharmacological treatment with antidepressants or antipsychotics for which a prolonged duration (5 years) of drug therapy was foreseen (46%) were included. The clinical variables collected by physicians of the psychiatry service included, among others, age, gender, ethnicity, diagnosis, medical comorbidities, type number and duration of psychiatric treatment, clinical global impression, and adverse drug reaction (UKU scale); physicians were blinded to genotype results. Regarding ethical issues, the Institutional Review Board of the University Hospital of Salamanca approved the study; all subjects gave written informed Editor: Zelena Dora. Received: July 27, 2015; revised: December 12, 2015; accepted: December 15, 2015. From the Servicio de Psiquiatrı́a, Hospital Universitario de Salamanca (SSI, CL-R, TM-P); Instituto Biosanitario de Salamanca, IBSAL (VG-S, BGB, AS-M, JML-R, MI-G); Servicio de Bioquı́mica Clı́nica, Hospital Universitario de Salamanca (BG-B, JMG-B, MI-G); Servicio de Farmacia, Hospital Universitario de Salamanca, Spain (AS-M); Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Children’s Mercy Hospital (AG); Department of Pediatrics, School of Medicine, University of Missouri-Kansas City, Kansas City, MO, USA (AG); and Departamento de Medicina, Universidad de Salamanca, Spain (MI-G). Correspondence: Marı́a Isidoro-Garcı́a, Department of Clinical Biochemistry, Hospital Universitario de Salamanca, Paseo de San Vicente 58, 37008 Salamanca, Spain (e-mail: misidoro@usal.es). The authors have no funding and conflicts of interest to disclose. Copyright # 2016 Wolters Kluwer Health, Inc. All rights reserved. This is an open access article distributed under the Creative Commons Attribution License 4.0, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. ISSN: 0025-7974 DOI: 10.1097/MD.0000000000002473 Medicine® QUALITY IMPROVEMENT STUDY Medicine Volume 95, Number 6, February 2016 www.md-journal.com | 1 consent to the genetic testing. Aspects related to privacy concerns, protection of participants, and physical well-being were addressed. Planing the Intervention The intervention planned here is based on the pharmacogenetics analysis of our patients by genotyping studies. P450 metabolizer enzymes are considered more likely to influence drug side effects. The intervention consisted in genotyping CYP2D6 gene in the psychiatric patients. The AmpliChip CYP450 Test (Roche Molecular Systems, In Indianapolis) approved by the Food and Drug Administration in 2005, was chosen because analyses 33 allelic variants of CYP2D6 including the most common variants observed across ethnicities. The majority of sequence variations detected are single nucleotide polymorphisms. The AmpliChip also detects the presence of a number of CYP2D6 gene duplications and the CYP2D6 5 gene deletion. Simultaneously, 2 additional single nucleotide polymorphisms are interrogated to determine the presence of CYP2C19 2 and 3. The analysis was prescribed by the psychiatrists after collecting the previous information and performed in the pharmacogenetics laboratory. DNA was extracted from 1 mL of whole blood collected into EDTAcontaining vacutainers with the MagnaPure Compact system (Roche Applied Science, Mannheim, Germany). AmpliChip CPY450 Test was performed as recommended by the manufacturer. Methods of Evaluation The intervention was developed in all patients included in the study. To assess how well the intervention was implemented clinical and laboratory supervision was established during all the study assigning a responsible for each task. It is expected that the intervention provides information that could be useful to predict adverse effects in these patients. To assure data quality, strict control and appropriate scales were used to data collection. In addition, the genotyping was performed following the directives of the European Molecular Genetics Management Network for DNA handling, with the requisite controls. The application of quality norms followed the UNE-EN-ISO 15189:2007 Normative in the Accredited Section of Molecular Genetics and Pharmacogenetics of the Clinical Biochemistry Service of the University Hospital in Salamanca. The normative included training and qualification of personal, preanalytical, analytical and postanalytical control, blinding, repeating measurements, and internal and external validity. Data Analyses Qualified statistical analysis was performed with SPSS v.17 (IBM, Chicago, IL, EEUU). For the analysis of the qualitative variables the Chi-square test was employed. In order to compare the qualitative and quantitative variables, ANOVA was performed after analysis of the homogeneity of variance. Determination of allele and genotype frequencies was accomplished with the Shesis platform. RESULTS Diagnostic categories observed in our cohort were schizophrenia and other psychotic disorders (F20–29) (n1⁄4 76, 33.9%); depressive disturbances (F32–34) (n1⁄4 72, 32.1%), BPD (F30–31) (n1⁄4 45, 20.1%), anxiety disorders (F40–43) (n1⁄4 16, 7.1%), and others psychiatric disorders (n1⁄4 15, 6.7%). The mean age of the patients was 45.3 years (SD 15.4) and 56.7% were women. The ethnicity of the subjects was predominantly Caucasian (95.8%). The intervention provided information about genotype distribution of CYP2D6 gene and the predicted phenotype. Of the 224 patients, 4.5% had CYP2D6 genotypes predicting UM, 9.8% IM, and 6.3% PM metabolizer phenotype. The most frequently observed genotypes were CYP2D6 1/ 2xN for UM group, 4/ 41 for IM group, and 4/ 4 in the PM group. Allele and genotype frequencies for the study cohort are shown in Tables 1 and 2. We did not find any correlations between metabolizer status and the studied disorders. For 6 patients the AmpliChip CPY450 Test returned ‘‘no-call’’ results that were solved by other methods. A total of 90.1% of the TABLE 1. Allelic Frequencies for CYP2D6 Gene in the Population Studied and in Normal Population CYP2D6 Alleles Predicted Enzyme Activity Caucasian Frequency, % Frequency, %y Number of Allelesy 1 Normal 33–37 38.53 168 4 None 12–23 19.72 86 2 Normal 22–33 16.74 73 41 Decreased 20 7.57 33 9 Decreased 0–3 4.59 20 2XN Increased <2 3.90 17 35 Normal 3–4 2.75 12 6 None <2 1.61 7 5 None 2–7 1