PMID- 33234666
OWN - NLM
STAT- MEDLINE
DCOM- 20210118
LR  - 20221207
IS  - 1098-4275 (Electronic)
IS  - 0031-4005 (Print)
IS  - 0031-4005 (Linking)
VI  - 146
IP  - 6
DP  - 2020 Dec
TI  - Pharmacogenetics to Predict Adverse Events Associated With Antidepressants.
LID - 10.1542/peds.2020-0957 [doi]
LID - e20200957
AB  - OBJECTIVES: To determine the association between cytochrome P450 2C19 (CYP2C19) 
      metabolizer status and risk for escitalopram and citalopram, collectively termed 
      (es)citalopram, and sertraline adverse events (AEs) in children. METHODS: In this 
      retrospective cohort study, we used deidentified electronic health records linked 
      to DNA. The cohort included children </=18 years with >/=2 days of (es)citalopram or 
      >/=7 days of sertraline exposure. The primary outcome was AEs assessed by manual 
      chart review. CYP2C19 was genotyped for functional variants (*2, *3, *4, *6, *8, 
      and *17), and individuals were assigned metabolizer status. Association between 
      AEs and metabolizer status was determined by using Cox regression adjusting for 
      age, race, ethnicity, dose, and concomitant CYP2C19-inhibiting medications. 
      RESULTS: The cohort included 249 sertraline-exposed and 458 
      (es)citalopram-exposed children, with a median age of 14.2 years (interquartile 
      range 11.2-16.2) and 13.4 years (interquartile range 10.1-15.9), respectively. 
      Sertraline AEs were more common in normal metabolizers (NMs) compared to poor 
      metabolizers (PMs) or intermediate metabolizers (IMs) (hazard ratio [HR] 1.8; 95% 
      confidence interval [CI] 1.01-3.2; P = .047) in unadjusted analysis and after 
      adjustment (HR 1.9; CI 1.04-3.4; P = .04). For (es)citalopram, more AEs were 
      observed in NMs than PMs and IMs without statistically significant differences 
      (unadjusted HR 1.6; CI 0.95-2.6; P = .08; adjusted HR 1.6; CI 0.95-2.6; P = .08). 
      CONCLUSIONS: In contrast to adults, in our pediatric cohort, CYP2C19 NMs 
      experienced increased sertraline AEs than PMs and IMs. (Es)citalopram AEs were 
      not associated with CYP2C19 status in the primary analysis. The mechanism 
      underlying this pediatric-specific finding is unknown but may be related to 
      physiologic differences of adolescence. Further research is required to inform 
      genotype-guided prescribing for these drugs in children.
CI  - Copyright (c) 2020 by the American Academy of Pediatrics.
FAU - Rossow, Katelyn M
AU  - Rossow KM
AD  - Departments of Pediatrics, katelyn.rossow@vumc.org.
AD  - Contributed equally as co-first authors.
FAU - Aka, Ida T
AU  - Aka IT
AD  - Departments of Pediatrics.
AD  - Contributed equally as co-first authors.
FAU - Maxwell-Horn, Angela C
AU  - Maxwell-Horn AC
AD  - Departments of Pediatrics.
FAU - Roden, Dan M
AU  - Roden DM
AD  - Medicine.
AD  - Pharmacology, and.
AD  - Biomedical Informatics, School of Medicine, Vanderbilt University, Nashville, 
      Tennessee.
FAU - Van Driest, Sara L
AU  - Van Driest SL
AD  - Departments of Pediatrics.
AD  - Medicine.
LA  - eng
GR  - T32 GM007569/GM/NIGMS NIH HHS/United States
GR  - UL1 TR000445/TR/NCATS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Video-Audio Media
PL  - United States
TA  - Pediatrics
JT  - Pediatrics
JID - 0376422
RN  - 0 (Antidepressive Agents)
RN  - 0 (Serotonin Uptake Inhibitors)
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP2C19)
SB  - IM
MH  - Adolescent
MH  - Antidepressive Agents/*adverse effects
MH  - Child
MH  - Cytochrome P-450 CYP2C19/*genetics/metabolism
MH  - Depression/*drug therapy/metabolism
MH  - Drug-Related Side Effects and Adverse Reactions/*genetics/metabolism
MH  - Female
MH  - Follow-Up Studies
MH  - Genotype
MH  - Humans
MH  - Male
MH  - Pharmacogenetics/*methods
MH  - Phenotype
MH  - *Polymorphism, Genetic
MH  - Retrospective Studies
MH  - Selective Serotonin Reuptake Inhibitors/adverse effects
PMC - PMC7786826
COIS- POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential 
      conflicts of interest to disclose.
EDAT- 2020/11/26 06:00
MHDA- 2021/01/20 06:00
PMCR- 2021/12/01
CRDT- 2020/11/25 05:37
PHST- 2020/09/02 00:00 [accepted]
PHST- 2020/11/26 06:00 [pubmed]
PHST- 2021/01/20 06:00 [medline]
PHST- 2020/11/25 05:37 [entrez]
PHST- 2021/12/01 00:00 [pmc-release]
AID - peds.2020-0957 [pii]
AID - 10.1542/peds.2020-0957 [doi]
PST - ppublish
SO  - Pediatrics. 2020 Dec;146(6):e20200957. doi: 10.1542/peds.2020-0957.