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Association of CYP2C19 and CYP2D6 Poor and Intermediate Metabolizer Status With Antidepressant and Antipsychotic Exposure: A Systematic Review and Meta-analysis

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Milosavljevic, Filip, Bukvic, Nikola, Pavlovic, Zorana, Miljevic, Cedo, Pešic, Vesna, Molden, Espen, Ingelman-Sundberg, Magnus, Leucht, Stefan, Jukic, Marin M.·2021·JAMA Psychiatry
DOI 10.1001/jamapsychiatry.2020.3643PMC PMC7702196
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Abstract

Importance: Precise estimation of the drug metabolism capacity for individual patients is crucial for adequate dose personalization. Objective: To quantify the difference in the antipsychotic and antidepressant exposure among patients with genetically associated CYP2C19 and CYP2D6 poor (PM), intermediate (IM), and normal (NM) metabolizers. Data Sources: PubMed, Clinicaltrialsregister.eu, ClinicalTrials.gov, International Clinical Trials Registry Platform, and CENTRAL databases were screened for studies from January 1, 1990, to June 30, 2020, with no language restrictions. Study Selection: Two independent reviewers performed study screening and assessed the following inclusion criteria: (1) appropriate CYP2C19 or CYP2D6 genotyping was performed, (2) genotype-based classification into CYP2C19 or CYP2D6 NM, IM, and PM categories was possible, and (3) 3 patients per metabolizer category were available. Data Extraction and Synthesis: The Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines were followed for extracting data and quality, validity, and risk of bias assessments. A fixed-effects model was used for pooling the effect sizes of the included studies. Main Outcomes and Measures: Drug exposure was measured as (1) dose-normalized area under the plasma level (time) curve, (2) dose-normalized steady-state plasma level, or (3) reciprocal apparent total drug clearance. The ratio of means (RoM) was calculated by dividing the mean drug exposure for PM, IM, or pooled PM plus IM categories by the mean drug exposure for the NM category. Results: Based on the data derived from 94 unique studies and 8379 unique individuals, the most profound differences were observed in the patients treated with aripiprazole (CYP2D6 PM plus IM vs NM RoM, 1.48; 95% CI, 1.41-1.57; 12 studies; 1038 patients), haloperidol lactate (CYP2D6 PM vs NM RoM, 1.68; 95% CI, 1.40-2.02; 9 studies; 423 patients), risperidone (CYP2D6 PM plus IM vs NM RoM, 1.36; 95% CI, 1.28-1.44; 23 studies; 1492 patients), escitalopram oxalate (CYP2C19 PM vs NM, RoM, 2.63; 95% CI, 2.40-2.89; 4 studies; 1262 patients), and sertraline hydrochloride (CYP2C19 IM vs NM RoM, 1.38; 95% CI, 1.27-1.51; 3 studies; 917 patients). Exposure differences were also observed for clozapine, quetiapine fumarate, amitriptyline hydrochloride, mirtazapine, nortriptyline hydrochloride, fluoxetine hydrochloride, fluvoxamine maleate, paroxetine hydrochloride, and venlafaxine hydrochloride; however, these differences were marginal, ambiguous, or based on less than 3 independent studies. Conclusions and Relevance: In this systematic review and meta-analysis, the association between CYP2C19/CYP2D6 genotype and drug levels of several psychiatric drugs was quantified with sufficient precision as to be useful as a scientific foundation for CYP2D6/CYP2C19 genotype-based dosing recommendations.

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Sorted by citations

Metadata

Authors
Milosavljevic, F., Bukvic, N., Pavlovic, Z., Miljevic, C., Pešic, V., Molden, E., Ingelman-Sundberg, M., Leucht, S., & Jukic, M. M.
Affiliations
  • Department of Physiology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia
  • Department of Psychiatry, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
  • University of Oslo (NO)
  • Pharmacogenetics Section, Department of Physiology and Pharmacology, Karolinska Institutet, Solna, Sweden
  • Technical University of Munich (DE)
ORCID
Venue
JAMA Psychiatry
Publisher
American Medical Association (AMA)
Published
2021-03-01
Volume
78
Issue
3
Pages
270
ISSN
2168-622X (ISSN-L)
DOI
10.1001/jamapsychiatry.2020.3643
PMC
PMC7702196
OpenAlex
W3107703675
Cited by
218
References
7
Citations by year
2026: 45 · 2025: 25 · 2024: 63 · 2023: 38 · 2022: 23 · 2021: 22
FWCI
3.00
Type
journal article
Language
en
Open access
Locations
  • JAMA Psychiatry (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • mediaTUM (Technical University of Munich) (submittedVersion)
Topics
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
Keywords
CYP2C19, CYP2D6, poor metabolizers, intermediate metabolizers, pharmacogenetics, antidepressants, antipsychotic drugs, drug exposure, aripiprazole, haloperidol, risperidone, clozapine, olanzapine, drug clearance, dose normalization
MeSH terms
Pharmacogenomic Variants, Antidepressive Agents, Humans, Antipsychotic Agents, Cytochrome P-450 CYP2D6, Cytochrome P-450 CYP2C19

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