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Original Investigation
November 25, 2020

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

Author Affiliations
  • 1Department of Physiology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia
  • 2Department of Psychiatry, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
  • 3Psychiatry Clinic, Clinical Centre of Serbia, Belgrade
  • 4Institute for Mental Health, Belgrade, Belgrade, Serbia
  • 5Department of Pharmacokinetics, University of Oslo Pharmacy School, Oslo, Norway
  • 6Pharmacogenetics Section, Department of Physiology and Pharmacology, Karolinska Institutet, Solna, Sweden
  • 7Department of Psychiatry and Psychotherapy, Technische Universität München School of Medicine, Munich, Germany
JAMA Psychiatry. 2021;78(3):270-280. doi:10.1001/jamapsychiatry.2020.3643
Key Points

Question  What is the difference in the expected antipsychotic and antidepressant exposure between genetically associated CYP2C19 and CYP2D6 poor (PM), intermediate (IM), and normal (NM) metabolism?

Findings  A systematic review and meta-analysis of 94 unique studies and 8379 unique patients quantified the increases of risperidone, aripiprazole, and haloperidol exposure in patients with CYP2D6 PM and IM status and increases of escitalopram and sertraline exposure in patients with CYP2C19 PM and IM status as compared with patients with the NM group.

Meaning  The obtained results represent a scientific foundation for CYP2D6/CYP2C19 genotype-based dosing recommendations that could potentially lead to improved clinical outcome in drug treatment for patients with psychiatric disorders.

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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