AUTHOR=Veldic Marin , Ahmed Ahmed T. , Blacker Caren J. , Geske Jennifer R. , Biernacka Joanna M. , Borreggine Kristin L. , Moore Katherine M. , Prieto Miguel L. , Vande Voort Jennifer L. , Croarkin Paul E. , Hoberg Astrid A. , Kung Simon , Alarcon Renato D. , Keeth Nicola , Singh Balwinder , Bobo William V. , Frye Mark A. 

TITLE=Cytochrome P450 2C19 Poor Metabolizer Phenotype in Treatment Resistant Depression: Treatment and Diagnostic Implications

JOURNAL=Frontiers in Pharmacology

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2019.00083

DOI=10.3389/fphar.2019.00083

ISSN=1663-9812

ABSTRACT=<p><bold>Background:</bold> Pharmacogenomic testing, specifically for pharmacokinetic (PK) and pharmacodynamic (PD) genetic variation, may contribute to a better understanding of baseline genetic differences in patients seeking treatment for depression, which may further impact clinical antidepressant treatment recommendations. This study evaluated PK and PD genetic variation and the clinical use of such testing in treatment seeking patients with bipolar disorder (BP) and major depressive disorder (MDD) and history of multiple drug failures/treatment resistance.</p><p><bold>Methods:</bold> Consecutive depressed patients evaluated at the Mayo Clinic Depression Center over a 10-year study time frame (2003–2013) were included in this retrospective analysis. Diagnoses of BP or MDD were confirmed using a semi-structured diagnostic interview. Clinical rating scales included the Hamilton Rating Scale for Depression (HRSD<sub>24</sub>), Generalized Anxiety Disorder 7-item scale (GAD-7), Patient Health Questionnaire-9 (PHQ-9), and Adverse Childhood Experiences (ACE) Questionnaire. Clinically selected patients underwent genotyping of cytochrome P450 <italic>CYP2D6</italic>/<italic>CYP2C19</italic> and the serotonin transporter <italic>SLC6A4</italic>. PK and PD differences and whether clinicians incorporated test results in providing recommendations were compared between the two patient groups.</p><p><bold>Results:</bold> Of the 1795 patients, 167/523 (31.9%) with BP and 446/1272 (35.1%) with MDD were genotyped. Genotyped patients had significantly higher self-report measures of depression and anxiety compared to non-genotyped patients. There were significantly more <italic>CYP2C19</italic> poor metabolizer (PM) phenotypes in BP (9.3%) vs. MDD patients (1.7%, <italic>p</italic> = 0.003); among participants with an S-allele, the rate of <italic>CYP2C19</italic> PM phenotype was even higher in the BP (9.8%) vs. MDD (0.6%, <italic>p</italic> = 0.003). There was a significant difference in the distribution of <italic>SLC6A4</italic> genotypes between BP (<italic>l/l</italic> = 28.1%, <italic>s/l</italic> = 59.3%, <italic>s/s</italic> = 12.6%) and MDD (<italic>l/l</italic> = 31.4%, <italic>s/l</italic> = 46.1%, <italic>s/s</italic> = 22.7%) patients (<italic>p</italic> &lt; 0.01).</p><p><bold>Conclusion:</bold> There may be underlying pharmacogenomic differences in treatment seeking depressed patients that potentially have impact on serum levels of <italic>CYP2C19</italic> metabolized antidepressants (i.e., citalopram / escitalopram) contributing to rates of efficacy vs. side effect burden with additional potential risk of antidepressant response vs. induced mania. The evidence for utilizing pharmacogenomics-guided therapy in MDD and BP is still developing with a much needed focus on drug safety, side effect burden, and treatment adherence.</p>