Pharmacogenetics in Child and Adolescent Psychiatry: Background and Evidence-Based Clinical Applications.

The efficacy and tolerability of psychotropic medications can vary significantly among children and adolescents, and some of this variability relates to pharmacogenetic factors. Pharmacogenetics (PGx) in child and adolescent psychiatry can potentially improve treatment outcomes and minimize adverse drug reactions. This article reviews key pharmacokinetic and pharmacodynamic genes and principles of pharmacogenetic testing and discusses the evidence base for clinical decision-making concerning PGx testing. This article reviews current guidelines from the United States Food and Drug Administration (FDA), the Clinical Pharmacogenetics Implementation Consortium (CPIC), and the Dutch Pharmacogenetics Working Group (DPWG) and explores potential future directions. This review discusses key clinical considerations for clinicians prescribing psychotropic medications in children and adolescents, focusing on antidepressants, antipsychotics, stimulants, norepinephrine reuptake inhibitors, and alpha-2 agonists. Finally, this review synthesizes the practical use of pharmacogenetic testing and clinical decision support systems.

Contrasting ABCB1 pharmacogenetics and psychotropic responses in child and adolescent psychiatry: a case comparison.

This case comparison illustrates pharmacogenetic testing in psychotropic and clinical management in relation to the ABCB1 gene, which encodes the P-glycoprotein transporter affecting blood-brain barrier (BBB) permeability. Two pediatric patients (9 and 11 years old) were selected for similar clinical presentations with opposing ABCB1 genotype, while they were identically matched for key CYP450, dopaminergic and serotonergic genes (CYP2C9, CYP2C19, DRD2, SLC6A4, 5HTR2A). Case A was functional for the ABCB1 gene (G/G rs1045642), suggesting that the BBB had a functional P-glycoprotein transporter. Case B was subfunctional for the ABCB1 gene (A/A rs1045642), suggesting that the patient's BBB may be permeable to psychotropic drugs. Case A had more medication trials and dose adjustments than Case B. Case A had two inpatient admissions and interspersed emergency room visits, while case B had none.

The focus of this case comparison report is the ABCB1 gene in child psychiatry and its role in drug efficacy and side effects. ABCB1 encodes the P-glycoprotein transporter of the blood­brain barrier (BBB). As antidepressants must cross the BBB to act on the brain, differences in the functionality of ABCB1 may lead to variable brain concentrations of antidepressants and subsequent variability in therapeutic response. Selecting the cases for comparison with opposing functionality at the ABCB1 gene, while matching for key CYP450, dopaminergic and serotonergic genes (CYP2C9, CYP2C19, DRD2, SLC6A4, 5HTR2A), was the approach utilized. The outcomes of case A and case B reflected pharmacogenetic and clinical contrasts, including patient responses to antidepressants and antipsychotics, susceptibility to adverse effects and differences in the severity of symptoms. These effects on antidepressants and antipsychotics are important because a permeable BBB will allow these drugs to cross into the brain to exert their effect, thus improving clinical outcomes, reducing hospitalizations and emergency room visits and minimizing drug trials and dosage changes. More clinical attention and research are needed for the BBB's involvement in psychiatric disease and for the P-glycoprotein transporter as a chemical gatekeeper to the brain. Pharmacogenetic testing for ABCB1 polymorphisms could be considered to inform psychotropic prescribing for the most vulnerable patients in child and adolescent psychiatry in the near future.

Editorial: Beyond Red Light, Green Light: Examining the Role of Pharmacogenomics in Evidence-Based Care in Child and Adolescent Psychiatry.

The role of pharmacogenetics in guiding psychopharmacologic treatment for children and adolescents remains elusive for many clinicians. In the absence of a solid and comprehensive evidence base, sufficient training, education, and consensus guidelines, commercial promotion of pharmacogenetic testing panels has the potential to become the main source of information for providers. Commonly, these tests include multigene panels and group medications into color-coded bins. These panels include both pharmacokinetic (PK) and pharmacodynamic (PD) genes and, using combinatorial algorithms, direct clinicians to use medications "as directed" or caution that "moderate gene-drug interaction(s)" or "significant gene-drug interaction(s)" may exist. Many industry-sponsored studies in adults have concluded that that when clinicians select medications based on pharmacogenomic guidance, patients have better outcomes,1 although some caution against this approach.2 To provide evidence on the clinical impact and potential of pharmacogenetic testing panels in clinical practice in child and adolescent psychiatry, in this issue of the Journal, Vande Voort3 and colleagues report the results of a prospective trial of pharmacogenetically guided treatment versus treatment as usual in depressed adolescents. The authors randomized adolescents aged 13 to 18 years with moderate to severe major depressive disorder (N = 176) to treatment guided by combinatorial pharmacogenetic testing that was either available at the baseline visit (GENE arm, n = 84) or at the 8-week visit (treatment-as-usual arm, n = 92). Patients and raters were blinded, but the treating psychiatrist was not blinded and could prescribe any medication deemed clinically indicated for the patient. Improvement, side effects, and satisfaction were assessed throughout the study and at a 6-month follow-up visit. There was no significant difference in terms of symptom improvement, side effect burden, or satisfaction at 8 weeks or 6 months between patients in the GENE and treatment-as-usual arms, respectively. However, significantly more patients in the treatment-as-usual arm received selective serotonin reuptake inhibitors (SSRIs) compared with patients in the GENE arm (81.5% vs 66.7%). Therefore, there was no significant clinical impact when clinicians used combinatorial pharmacogenomic testing to guide treatment for depressed adolescents. If anything, this guidance influenced providers to more frequently prescribe medications that are not considered first-line for the treatment of depression in youths (serotonin-norepinephrine reuptake inhibitors [SNRIs], atypical antidepressants) and for which double-blind placebo-controlled trials have failed to demonstrate efficacy in depressed youths.4,5.

Thoughtful Clinical Use of Pharmacogenetics in Child and Adolescent Psychopharmacology.

AACAP's recent policy statement on Clinical Use of Pharmacogenetic Tests in Prescribing Psychotropic Medications for Children and Adolescents1 recommends that "clinicians avoid using pharmacogenetic testing to select psychotropic medications in children and adolescents." We agree that there are limitations to the nascent evidence base for using pharmacogenetics, especially in combinatorial form (eg, test results that bin medications based on multiple genes). However, all-or-nothing recommendations fail to recognize the nuance and context of this testing and contrast with the AACAP Facts for Families on pharmacogenetic testing. Moreover, pharmacogenetic testing may inform dosing for antidepressants that are commonly used in child and adolescent psychiatry (eg, sertraline, escitalopram, citalopram, fluvoxamine) as well as the tolerability of some psychotropic medications. With this in mind, we wish to remind the AACAP community of the accumulating evidence and to highlight important principles of pharmacogenetic testing in youths. Specifically: 1) pharmacogenetic testing is not always performed by commercial companies and is not always combinatorial; 2) dosing recommendations or assessment of risk for severe hypersensitivity reactions are based on pharmacogenetics in the Food and Drug Administration (FDA)-approved product inserts for several medications commonly prescribed to children (eg, citalopram, aripiprazole, atomoxetine, carbamazepine, oxcarbazepine at www.fda.gov/drugs/science-and-research-drugs/table-pharmacogenomic-biomarkers-drug-labeling); 3) expert consensus guidelines for dosing or identifying hypersensitivity risk for these drugs are available from the National Institutes of Health (NIH)-supported Clinical Pharmacogenetics Implementation Consortium (CPIC, www.cpicpgx.org/), which provides transparent, regularly updated, and evidence-based evaluations of pharmacogenetic data;2 and 4) randomized trials are not required for clinical dose adjustments; for example, dose adjustments because of decreased hepatic function or concomitant interacting medications are based on pharmacokinetic data, similar to many pharmacokinetic gene-based recommendations from CPIC.

Pharmacogenomics: an Update for Child and Adolescent Psychiatry.

PURPOSE OF REVIEW: This paper aims to acquaint child and adolescent psychiatrists with the field of pharmacogenomics (PGX) and review the most up-to-date evidence-based practices to guide the application of this field in clinical care. RECENT FINDINGS: Despite much research being done in this area, the field of PGX continues to yield controversial findings. In the adult world, studies have focused on the impact of combinatorial gene panels that guide medication selection by providing reports that estimate the impact of multiple pharmacodynamic and pharmacokinetic genes, but to date, these have not been directly examined in younger patient populations. Pharmacokinetic genes, CYP2D6 and CYP2C19, and hypersensitivity genes, HLA-A and HLA-B, have the strongest evidence base for application to pharmacotherapy in children. Although the field is evolving, and the evidence is mixed, there may be a role for PGX testing in children to help guide dosing and monitoring strategies. However, evidence-based medicine, rather than PGX testing, continues to play the lead role in guiding medication selection in pediatric psychopharmacology.

Pain Amplification Syndrome: A Biopsychosocial Approach.

Pediatric neurologists frequently encounter patients who present with significant musculoskeletal pain that cannot be attributed to a specific injury or illness, which can often be defined as pain amplification syndrome (PAS). PAS in children and adolescents is the result of a heightened pain sensitivity pathway, which is intensified by significant biological, psychological, and social contributors. Appropriate assessment and multimodal intervention of PAS are crucial to treatment success, including neurology and behavioral health collaborative treatment plans to restore patient function and reduce pain perception. Pediatric neurologists are imperative in the identification of patients with PAS, providing the family assurance in diagnosis and validation of pain, and directing patients to the appropriate multidisciplinary treatment pathway.

Targeting symptom domains: a strategy for pharmacotherapy in childhood pervasive developmental disorders.

This article summarizes clinical guidelines and reviews psychopharmacologic studies involving children and adolescents with Pervasive Developmental Disorders (PDDs). Strategies are drawn from basic principles of pediatric psychopharmacology, nonpharmacological approaches to the treatment of PDDs, and practical clinical experience in an attempt to provide the practitioner with an evidence-based approach to utilizing pharmacotherapy in children and adolescents with PDDs. Although early identification followed by intensive educational and behavioral interventions remains the essential treatment of PDDs, there is evidence to support the identification of target behaviors or symptom domains, for medication. Evidence-based medicine (EBM) is then used to guide pharmacotherapy with the overall goal of optimizing the benefits of multidisciplinary treatment interventions.

Use of citalopram in pervasive developmental disorders.

This study assessed the effectiveness and tolerability of the selective serotonin reuptake inhibitor citalopram in the treatment of patients with pervasive developmental disorders (PDDs). The medical charts of 15 children and adolescents (aged 6-16 yr) with Asperger syndrome, autism, or PDD not otherwise specified treated with citalopram were retrospectively reviewed. The final dose of citalopram was 16.9 +/- 12.1 mg/day with a treatment duration of 218.8 +/- 167.2 days. Independent ratings of the Clinical Global Impression (CGI) Severity and Improvement scales allowed comparison between baseline and PDD symptoms at the last visit. Eleven adolescents (73%) exhibited significant improvement in PDD, anxiety, or mood CGI score (z = 2.95; p =.003). Anxiety symptoms associated with PDDs improved significantly in 66% of patients (z = 2.83, p =.005), and mood symptoms improved significantly in 47% of patients (z = 2.78, p =.005). Mild side effects were reported by five patients (33%). These data suggest citalopram may be effective, safe, and well tolerated as part of the treatment of PDDs.