Cytochrome P450 2C19 poor metabolizer phenotype in treatment resistant depression: Treatment and diagnostic implications

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

Research output: Contribution to journalArticle

Abstract

Background: 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. Methods: 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 (HRSD24), 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 CYP2D6/CYP2C19 and the serotonin transporter SLC6A4. PK and PD differences and whether clinicians incorporated test results in providing recommendations were compared between the two patient groups. Results: 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 CYP2C19 poor metabolizer (PM) phenotypes in BP (9.3%) vs. MDD patients (1.7%, p = 0.003); among participants with an S-allele, the rate of CYP2C19 PM phenotype was even higher in the BP (9.8%) vs. MDD (0.6%, p = 0.003). There was a significant difference in the distribution of SLC6A4 genotypes between BP (l/l = 28.1%, s/l = 59.3%, s/s = 12.6%) and MDD (l/l = 31.4%, s/l = 46.1%, s/s = 22.7%) patients (p < 0.01). Conclusion: There may be underlying pharmacogenomic differences in treatment seeking depressed patients that potentially have impact on serum levels of CYP2C19 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.

Original languageEnglish (US)
Article number83
JournalFrontiers in Pharmacology
Volume10
Issue numberFEB
DOIs
StatePublished - Jan 1 2019

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Treatment-Resistant Depressive Disorder
Cytochrome P-450 Enzyme System
Phenotype
Bipolar Disorder
Major Depressive Disorder
Therapeutics
Depression
Antidepressive Agents
Citalopram
Pharmacokinetics
Pharmacogenetics
Cytochrome P-450 CYP2D6
Serotonin Plasma Membrane Transport Proteins
Anxiety Disorders
Drug-Related Side Effects and Adverse Reactions
Treatment Failure
Self Report

Keywords

  • Bipolar disorder
  • CYP2C19
  • Cytochrome P450
  • Pharmacogenomics
  • SLC6A4

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

Cytochrome P450 2C19 poor metabolizer phenotype in treatment resistant depression : Treatment and diagnostic implications. / Veldic, Marin D; Ahmed, Ahmed T.; Blacker, Caren J.; Geske, Jennifer R.; Biernacka, Joanna M; Borreggine, Kristin L.; Moore, Katherine M.; Prieto, Miguel L.; Vande Voort, Jennifer; Croarkin, Paul E; Hoberg, Astrid A.; Kung, Simon; Alarcon, Renato D.; Keeth, Nicola; Singh, Balwinder; Bobo, William V; Frye, Mark A.

In: Frontiers in Pharmacology, Vol. 10, No. FEB, 83, 01.01.2019.

Research output: Contribution to journalArticle

Veldic, Marin D ; Ahmed, Ahmed T. ; Blacker, Caren J. ; Geske, Jennifer R. ; Biernacka, Joanna M ; Borreggine, Kristin L. ; Moore, Katherine M. ; Prieto, Miguel L. ; Vande Voort, Jennifer ; Croarkin, Paul E ; Hoberg, Astrid A. ; Kung, Simon ; Alarcon, Renato D. ; Keeth, Nicola ; Singh, Balwinder ; Bobo, William V ; Frye, Mark A. / Cytochrome P450 2C19 poor metabolizer phenotype in treatment resistant depression : Treatment and diagnostic implications. In: Frontiers in Pharmacology. 2019 ; Vol. 10, No. FEB.
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abstract = "Background: 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. Methods: 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 (HRSD24), 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 CYP2D6/CYP2C19 and the serotonin transporter SLC6A4. PK and PD differences and whether clinicians incorporated test results in providing recommendations were compared between the two patient groups. Results: 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 CYP2C19 poor metabolizer (PM) phenotypes in BP (9.3{\%}) vs. MDD patients (1.7{\%}, p = 0.003); among participants with an S-allele, the rate of CYP2C19 PM phenotype was even higher in the BP (9.8{\%}) vs. MDD (0.6{\%}, p = 0.003). There was a significant difference in the distribution of SLC6A4 genotypes between BP (l/l = 28.1{\%}, s/l = 59.3{\%}, s/s = 12.6{\%}) and MDD (l/l = 31.4{\%}, s/l = 46.1{\%}, s/s = 22.7{\%}) patients (p < 0.01). Conclusion: There may be underlying pharmacogenomic differences in treatment seeking depressed patients that potentially have impact on serum levels of CYP2C19 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.",
keywords = "Bipolar disorder, CYP2C19, Cytochrome P450, Pharmacogenomics, SLC6A4",
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TY - JOUR

T1 - Cytochrome P450 2C19 poor metabolizer phenotype in treatment resistant depression

T2 - Treatment and diagnostic implications

AU - Veldic, Marin D

AU - Ahmed, Ahmed T.

AU - Blacker, Caren J.

AU - Geske, Jennifer R.

AU - Biernacka, Joanna M

AU - Borreggine, Kristin L.

AU - Moore, Katherine M.

AU - Prieto, Miguel L.

AU - Vande Voort, Jennifer

AU - Croarkin, Paul E

AU - Hoberg, Astrid A.

AU - Kung, Simon

AU - Alarcon, Renato D.

AU - Keeth, Nicola

AU - Singh, Balwinder

AU - Bobo, William V

AU - Frye, Mark A

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Background: 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. Methods: 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 (HRSD24), 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 CYP2D6/CYP2C19 and the serotonin transporter SLC6A4. PK and PD differences and whether clinicians incorporated test results in providing recommendations were compared between the two patient groups. Results: 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 CYP2C19 poor metabolizer (PM) phenotypes in BP (9.3%) vs. MDD patients (1.7%, p = 0.003); among participants with an S-allele, the rate of CYP2C19 PM phenotype was even higher in the BP (9.8%) vs. MDD (0.6%, p = 0.003). There was a significant difference in the distribution of SLC6A4 genotypes between BP (l/l = 28.1%, s/l = 59.3%, s/s = 12.6%) and MDD (l/l = 31.4%, s/l = 46.1%, s/s = 22.7%) patients (p < 0.01). Conclusion: There may be underlying pharmacogenomic differences in treatment seeking depressed patients that potentially have impact on serum levels of CYP2C19 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.

AB - Background: 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. Methods: 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 (HRSD24), 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 CYP2D6/CYP2C19 and the serotonin transporter SLC6A4. PK and PD differences and whether clinicians incorporated test results in providing recommendations were compared between the two patient groups. Results: 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 CYP2C19 poor metabolizer (PM) phenotypes in BP (9.3%) vs. MDD patients (1.7%, p = 0.003); among participants with an S-allele, the rate of CYP2C19 PM phenotype was even higher in the BP (9.8%) vs. MDD (0.6%, p = 0.003). There was a significant difference in the distribution of SLC6A4 genotypes between BP (l/l = 28.1%, s/l = 59.3%, s/s = 12.6%) and MDD (l/l = 31.4%, s/l = 46.1%, s/s = 22.7%) patients (p < 0.01). Conclusion: There may be underlying pharmacogenomic differences in treatment seeking depressed patients that potentially have impact on serum levels of CYP2C19 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.

KW - Bipolar disorder

KW - CYP2C19

KW - Cytochrome P450

KW - Pharmacogenomics

KW - SLC6A4

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