Pediatric considerations for pharmacogenetic selective serotonin reuptake inhibitors clinical decision support.

Pharmacogenetic testing for psychiatry is growing at a rapid pace, with multiple sites utilizing results to help clinical decision-making. Genotype-guided dosing and drug selection have been implemented at several sites, including Vanderbilt University Medical Center, where clinical decision support (CDS) based on pharmacogenetic results went live for selective serotonin reuptake inhibitors in 2020 for both adult and pediatric patients. Effective and appropriate implementation of CYP2D6- and CYP2C19-guided CDS for the pediatric population requires consideration of the evidence for the pharmacogenetic associations, medication indications, and appropriate alternative therapies to be used when a pharmacogenetic contraindication is identified. In this article, we review these pediatric pharmacogenetic considerations for selective serotonin reuptake inhibitor CDS. We include a case study, the current literature supporting clinical recommendations, considerations when designing pediatric CDS, future implications, and examples of sertraline, (es)citalopram, paroxetine, and fluvoxamine alerts.

Direct Measures of Medication Effects: Exploring the Scientific Utility of Behavior-Analytic Assessments.

The purpose of the current study was to explore the scientific utility of two behavior analytic assessments (i.e., progressive ratio and demand assessments) for psychotropic medication evaluation. For a sample of 23 children with disabilities who were prescribed medication, we conducted a series of generalizability and optimization studies to identify sources of score variance and conditions in which stable estimates of behavior can be obtained. To inform construct validity, we calculated correlations between scores from each assessment and those from a standardized behavior rating scale (Aberrant Behavior Checklist-Second Edition; ABC-2). Results offer initial support for the scientific utility of progressive ratio scores. More research is needed to evaluate sensitivity to change and construct validity of scores from these and other behavior analytic assessments.

Evidence for Pharmacogenomic Effects on Risperidone Outcomes in Pediatrics.

OBJECTIVE: To determine the association between genetic variants reported to affect risperidone and adverse events (AEs) in children and adolescents. METHODS: Individuals aged 18 years or younger with ≥4 weeks of risperidone exposure in a deidentified DNA biobank were included. The primary outcome was AE frequency as a function of genotype. Individuals were classified according to metabolizer status for CYP2D6, CYP3A4, and CYP3A5; wild type, heterozygote, or homozygote for specific single nucleotide variants for DRD2, DRD3, HTR2A, and HTR2C; and wild type versus nonwild type for multiple uncommon variants in ABCG2, ABCB1, and HTR2C. Tests of association of each classification to AEs were performed using a Fisher exact test and logistic regression, and statistically significant classifications were included in a final logistic regression. RESULTS: The final cohort included 257 individuals. AEs were more common in CYP2D6 poor/intermediate metabolizers (PMs/IMs) than normal/rapid/ultrarapid metabolizers (NMs/RMs/UMs) in univariate and multivariate analysis. HTR2A-rs6311 heterozygotes and homozygotes had fewer AEs than wild types in logistic regression but not in univariate analysis. In the final multivariable model adjusting for age, race, sex, and risperidone dose, AEs were associated with CYP2D6 (adjusted odds ratio [AOR] 2.6, 95% CI 1.1-5.5, for PMs/IMs vs. NMs/RMs/UMs) and HTR2A-rs6311 (AOR 0.6, 95% CI 0.4-0.9, for each variant allele), both consistent with previous studies. CONCLUSION: Children and adolescents who are CYP2D6 PMs/IMs may have an increased risk for risperidone AEs. Of the genes and variants studied, only CYP2D6 has consistent association and sufficient data for clinical use, whereas HTR2A-rs6311 has limited data and requires further study.

Pharmacogenetics to Predict Adverse Events Associated With Antidepressants.

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.

CYP2D6 genotype and adverse events to risperidone in children and adolescents.

BACKGROUND: There are few and conflicting data on the role of cytochrome P450 2D6 (CYP2D6) polymorphisms in relation to risperidone adverse events (AEs) in children. This study assessed the association between CYP2D6 metabolizer status and risk for risperidone AEs in children. METHODS: Children ≤18 years with at least 4 weeks of risperidone exposure were identified using BioVU, a de-identified DNA biobank linked to electronic health record data. The primary outcome of this study was AEs. After DNA sequencing, individuals were classified as CYP2D6 poor, intermediate, normal, or ultrarapid CYP2D6 metabolizers. RESULTS: For analysis, the 257 individuals were grouped as poor/intermediate metabolizers (n = 33, 13%) and normal/ultrarapid metabolizers (n = 224, 87%). AEs were more common in poor/intermediate vs. normal/ultrarapid metabolizers (15/33, 46% vs. 61/224, 27%, P = 0.04). In multivariate analysis adjusting for age, sex, race, and initial dose, poor/intermediate metabolizers had increased AE risk (adjusted odds ratio 2.4, 95% confidence interval 1.1-5.1, P = 0.03). CONCLUSION: Children with CYP2D6 poor or intermediate metabolizer phenotypes are at greater risk for risperidone AEs. Pre-prescription genotyping could identify this high-risk subset for an alternate therapy, risperidone dose reduction, and/or increased monitoring for AEs.

Clinical Pharmacogenetics of Cytochrome P450-Associated Drugs in Children.

Cytochrome P450 (CYP) enzymes are commonly involved in drug metabolism, and genetic variation in the genes encoding CYPs are associated with variable drug response. While genotype-guided therapy has been clinically implemented in adults, these associations are less well established for pediatric patients. In order to understand the frequency of pediatric exposures to drugs with known CYP interactions, we compiled all actionable drug-CYP interactions with a high level of evidence using Clinical Pharmacogenomic Implementation Consortium (CPIC) data and surveyed 10 years of electronic health records (EHR) data for the number of children exposed to CYP-associated drugs. Subsequently, we performed a focused literature review for drugs commonly used in pediatrics, defined as more than 5000 pediatric patients exposed in the decade-long EHR cohort. There were 48 drug-CYP interactions with a high level of evidence in the CPIC database. Of those, only 10 drugs were commonly used in children (ondansetron, oxycodone, codeine, omeprazole, lansoprazole, sertraline, amitriptyline, citalopram, escitalopram, and risperidone). For these drugs, reports of the drug-CYP interaction in cohorts including children were sparse. There are adequate data for implementation of genotype-guided therapy for children for three of the 10 commonly used drugs (codeine, omeprazole and lansoprazole). For the majority of commonly used drugs with known CYP interactions, more data are required to support pharmacogenomic implementation in children.

Sleep in Autism Spectrum Disorders.

Autism spectrum disorders (ASD) are common neurodevelopmental conditions, affecting 1 in 68 children. Sleep disturbance, particularly insomnia, is very common in children diagnosed with ASD, with evidence supporting overlapping neurobiological and genetic underpinnings. Disturbed sleep exacerbates core and related ASD symptoms and has a substantial negative impact on the entire family. Treatment of sleep disturbance holds promise for ameliorating many of the challenging behavioral symptoms that children with ASD and their families face. Behavioral and pharmacological studies indicate promising approaches to treating sleep disturbances in this population. Awareness of treatment options is particularly important as parents and clinicians may believe that sleep disturbance is part of autism and refractory to therapy. In addition, autism symptoms refractory to treatment with conventional psychiatric medications may improve when sleep is addressed. Additional evidence-based studies are needed, including those that address the underlying biology of this condition.