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Pharmacogenetic testing in children: What to test and how to use it

Current Psychiatry. 2018 September;17(9):30-36
September 1, 2018|Psychiatry
Laura B. Ramsey, PhD
Author and Disclosure Information

Laura B. Ramsey, PhD
Assistant Professor
Divisions of Research in Patient Services & Clinical Pharmacology
Cincinnati Children’s Hospital Medical Center
Department of Pediatrics
University of Cincinnati
Cincinnati, Ohio

Disclosure
The author reports no financial relationships with any company whose products are mentioned in this article, or with manufacturers of competing products.

Pediatric-specific evidence is limited, but testing can inform treatment, improve outcomes

Guidelines help with genotype-guided dosing

Antipsychotics: Pharmacogenetic guidelines and metabolizing enzymes
The Clinical Pharmacogenetics Implemen­tation Consortium (CPIC) has published guidelines describing the allele definitions, allele activity, and phenotypic interpretation.14 Evidence-based guidelines for genotype-guided dosing of selective serotonin reuptake inhibitors (SSRIs)4 and tricyclic antidepressants5,15 are available from CPIC. There is less guidance for antipsychotics, although the Dutch Pharmacogenetics Working Group (DPWG) provides some guidance for aripiprazole and haloperidol.6,7

Each CPIC guideline specifically addresses use in pediatric patients, indicating that there are relatively few studies in pediatrics, but “it may be appropriate to extrapolate these recommendations to adolescents or possibly younger children with close monitoring.”4 The DPWG guidelines do not mention whether or not the recommendations are applicable to children. Neither CPIC nor the DPWG provides guidance on when to test; however, the French National Network of Pharmacogenetics (Réseau national de pharmacogénétique) recommends CYP2D6 and CYP2C19 genotyping before initiating antidepressant treatment, especially in patients with a high risk of toxicity.16

In the case above, Ms. R was determined to be a CYP2D6 ultra-rapid metabolizer. Because she showed some initial response to aripiprazole and venlafaxine ER, which are both metabolized by CYP2D6, these medications were very quickly titrated up, and the increased dosages produced the desired response. Venlafaxine is metabolized to the active metabolite O-desmethylvenlafaxine by CYP2D6. The DPWG recommends increasing the dose of venlafaxine in CYP2D6 ultra-rapid metabolizers to 150% of the normal dose based on the decreased serum concentrations of venlafaxine and O-desmethylvenlafaxine in these patients.6 Aripiprazole is also metabolized by CYP2D6; however, the FDA and DPWG give no recommendations for ultra-rapid metabolizers, but do recommend reducing the dose of aripiprazole in CYP2D6 poor metabolizers.

Multiple studies in adults have analyzed the association between pharmacokinetic (CYP2D6 and CYP2C19) or pharmacodynamic genes (SLC6A4, HTR2A, and GRIK4) and outcomes,17 including some large clinical trials that conducted genome-wide association studies18-20 and meta-analyses across multiple studies.21,22 Most pharmacogenetic studies in psychiatric patients are small, and very few have included pediatric patients. However, with more interest in neuropsychiatric pharmacogenetics, these studies are becoming more common.23-26

Continue to: Limited evidence from studies of commercially available tests

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