Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6, CYP2C19, CYP2B6, SLC6A4, and HTR2A Genotypes and Serotonin Reuptake Inhibitor Antidepressants

Chad A Bousman; James M Stevenson; Laura B Ramsey; Katrin Sangkuhl; J Kevin Hicks; Jeffrey R Strawn; Ajeet B Singh; Gualberto Ruaño; Daniel J Mueller; Evangelia Eirini Tsermpini; Jacob T Brown; Gillian C Bell; J Steven Leeder; Andrea Gaedigk; Stuart A Scott; Teri E Klein; Kelly E Caudle; Jeffrey R Bishop

doi:10.1002/cpt.2903

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6, CYP2C19, CYP2B6, SLC6A4, and HTR2A Genotypes and Serotonin Reuptake Inhibitor Antidepressants

Clin Pharmacol Ther. 2023 Jul;114(1):51-68. doi: 10.1002/cpt.2903. Epub 2023 May 30.

Authors

Chad A Bousman^{1

2

3

4

5

6}, James M Stevenson^{7

8}, Laura B Ramsey^{9

10

11}, Katrin Sangkuhl¹², J Kevin Hicks¹³, Jeffrey R Strawn^{11

14

15}, Ajeet B Singh¹⁶, Gualberto Ruaño^{17

18}, Daniel J Mueller^{19

20}, Evangelia Eirini Tsermpini²¹, Jacob T Brown²², Gillian C Bell²³, J Steven Leeder^{24

25}, Andrea Gaedigk^{24

25}, Stuart A Scott^{26

27}, Teri E Klein¹², Kelly E Caudle²⁸, Jeffrey R Bishop^{29

30}

Affiliations

¹ Department of Medical Genetics, University of Calgary, Calgary, Alberta, Canada.
² Department of Psychiatry, University of Calgary, Calgary, Alberta, Canada.
³ Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada.
⁴ Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada.
⁵ Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada.
⁶ Mathison Centre for Mental Health Research and Education, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.
⁷ Division of Clinical Pharmacology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
⁸ Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
⁹ Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
¹⁰ Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
¹¹ Division of Patient Services, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
¹² Department of Biomedical Data Science, Stanford University, Stanford, California, USA.
¹³ Department of Individualized Cancer Management, Moffitt Cancer Center, Tampa, Florida, USA.
¹⁴ Department of Psychiatry & Behavioral Neuroscience, University of Cincinnati, Cincinnati, Ohio, USA.
¹⁵ Division of Child & Adolescent Psychiatry, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
¹⁶ School of Medicine, IMPACT Institute, Deakin University, Burwood, Victoria, Australia.
¹⁷ Institute of Living at Hartford Hospital, Hartford, Connecticut, USA.
¹⁸ Department of Psychiatry, University of Connecticut School of Medicine, Farmington, Connecticut, USA.
¹⁹ Pharmacogenetics Research Clinic, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
²⁰ Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
²¹ Pharmacogenetics Laboratory, Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
²² Department of Pharmacy Practice & Pharmaceutical Sciences, University of Minnesota College of Pharmacy, Duluth, Minnesota, USA.
²³ Genome Medical, South San Francisco, California, USA.
²⁴ Division of Clinical Pharmacology, Toxicology & Therapeutic Innovation, Children's Mercy Research Institute, Kansas City, Missouri, USA.
²⁵ School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri, USA.
²⁶ Department of Pathology, Stanford University, Palo Alto, California, USA.
²⁷ Stanford Medicine Clinical Genomics Program, Stanford Medicine, Stanford, California, USA.
²⁸ Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
²⁹ Department of Experimental and Clinical Pharmacology, University of Minnesota College of Pharmacy, Minneapolis, Minnesota, USA.
³⁰ Department of Psychiatry and Behavioral Sciences, University of Minnesota Medical School, Minneapolis, Minnesota, USA.

Abstract

Serotonin reuptake inhibitor antidepressants, including selective serotonin reuptake inhibitors (SSRIs; i.e., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline), serotonin and norepinephrine reuptake inhibitors (i.e., desvenlafaxine, duloxetine, levomilnacipran, milnacipran, and venlafaxine), and serotonin modulators with SSRI-like properties (i.e., vilazodone and vortioxetine) are primary pharmacologic treatments for major depressive and anxiety disorders. Genetic variation in CYP2D6, CYP2C19, and CYP2B6 influences the metabolism of many of these antidepressants, which may potentially affect dosing, efficacy, and tolerability. In addition, the pharmacodynamic genes SLC6A4 (serotonin transporter) and HTR2A (serotonin-2A receptor) have been examined in relation to efficacy and side effect profiles of these drugs. This guideline updates and expands the 2015 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 and CYP2C19 genotypes and SSRI dosing and summarizes the impact of CYP2D6, CYP2C19, CYP2B6, SLC6A4, and HTR2A genotypes on antidepressant dosing, efficacy, and tolerability. We provide recommendations for using CYP2D6, CYP2C19, and CYP2B6 genotype results to help inform prescribing these antidepressants and describe the existing data for SLC6A4 and HTR2A, which do not support their clinical use in antidepressant prescribing.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Practice Guideline

MeSH terms

Antidepressive Agents / therapeutic use
Citalopram / therapeutic use
Cytochrome P-450 CYP2B6 / genetics
Cytochrome P-450 CYP2C19 / genetics
Cytochrome P-450 CYP2C19 / metabolism
Cytochrome P-450 CYP2D6 / genetics
Cytochrome P-450 CYP2D6 / metabolism
Depressive Disorder, Major* / drug therapy
Depressive Disorder, Major* / genetics
Genotype
Humans
Pharmacogenetics
Selective Serotonin Reuptake Inhibitors*
Serotonin
Serotonin Plasma Membrane Transport Proteins / genetics

Substances

Selective Serotonin Reuptake Inhibitors
Cytochrome P-450 CYP2D6
Cytochrome P-450 CYP2B6
Cytochrome P-450 CYP2C19
Serotonin Plasma Membrane Transport Proteins
Serotonin
Antidepressive Agents
Citalopram
CYP2B6 protein, human
CYP2C19 protein, human
SLC6A4 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding