Ensuring equity: Pharmacogenetic implementation in rural and tribal communities.

Implementation strategies for pharmacogenetic testing have been largely limited to major academic medical centers and large health systems, threatening to exacerbate healthcare disparities for rural and tribal populations. There exists a need in Montana (United States)-a state where two-thirds of the population live in rural areas and with a large proportion of tribal residents-to develop novel strategies to make pharmacogenetic testing more broadly available. We established partnerships between University of Montana (UM) and three early adopter sites providing patient-centered care to historically neglected populations. We conducted 45 semi-structured interviews with key stakeholders at each site and solicited participant feedback on the utility of a centralized pharmacogenetic service at UM offering consultations to patients and providers statewide via telehealth. For settings serving rural patients-tribal and non-tribal-participants described healthcare facilities without adequate infrastructure, personnel, and funding to implement pharmacogenetic services. Participants serving tribal communities stressed the need for ethical practices for collecting biospecimens and returning genetic results to patients, largely due to historical and contemporary traumas experienced by tribal populations with regard to genetic research. Participants expressed that pharmacogenetic testing could benefit patients by achieving therapeutic benefit sooner, reducing the risk of side effects, and improving adherence outcomes for patients with limited access to follow-up services in remote areas. Others expressed concern that financial barriers to pharmacogenetic testing for patients of lower socioeconomic status would further exacerbate inequities in care. Participants valued the role of telehealth to deliver pharmacogenetic consults from a centralized service at UM, describing the ability to connect providers and patients to resources and expertise as imperative to driving successful pharmacogenetic implementation. Our results support strategies to improve access to pharmacogenetic testing for neglected patient populations and create opportunities to reduce existing healthcare inequities. By exploring critical challenges for pharmacogenetic implementation focused on serving underserved communities, this work can help guide equitable frameworks to serve as a model for other resource-limited settings looking to initiate pharmacogenetic testing.

Possible Oxcarbazepine Inductive Effects on Aripiprazole Metabolism: A Case Report.

Oxcarbazepine is a cytochrome P450 (CYP) 3A4 inducer, which is structurally similar to carbamazepine. Although lacking Food and Drug Administration approval, oxcarbazepine is sometimes prescribed to treat aggressive behavior in youth with autism spectrum disorder (ASD). These youths may also be taking second-generation antipsychotics, some of which are substrates of the CYP3A4 metabolic pathway. The combination of these medications may result in decreased serum antipsychotic concentrations, potentially reducing effectiveness. A limited number of reports are available which discuss reduced atypical antipsychotic concentrations secondary to oxcarbazepine CYP3A4 induction. We report a young boy taking oxcarbazepine (1200 mg/d) who presented with an unexpectedly low serum aripiprazole concentration. Utilizing therapeutic drug monitoring, pharmacogenetic testing, and a tool to evaluate drug-drug interactions, we estimate that oxcarbazepine possibly reduced his serum aripiprazole concentration by 68%. Our report is important, as it is the first to describe a drug-drug interaction between oxcarbazepine and aripiprazole. This report should encourage the completion of in vitro and clinical studies and the publication of case reports describing the possible inductive effects of oxcarbazepine on atypical antipsychotics (including cariprazine, lurasidone, quetiapine, aripiprazole, brexpiprazole, iloperidone, and risperidone) mediated by induction of the CYP3A4 metabolic pathway.

Adjunctive Amantadine Treatment for Aggressive Behavior in Children: A Series of Eight Cases.

PURPOSE: Amantadine has a growing body of evidence for the treatment of aggressive behavior in patients with traumatic brain injury, autism spectrum disorder, and developmental disability. We describe our experience with adjunctive amantadine treatment for aggressive behavior in eight hospitalized children. METHODS: We conducted a retrospective chart review of psychiatric inpatients initiated on amantadine for the management of aggressive behavior. RESULTS: The majority of patients were male (n = 7) ranging in age from 6 to 10 years (mean 8.5). The most common diagnoses were attention-deficit/hyperactivity disorder (n = 6), intermittent explosive disorder (n = 4), oppositional defiant disorder (n = 4), and bipolar disorder (n = 3). Five patients had either borderline intellectual functioning or an unspecified cognitive disorder, and four patients had either confirmed or suspected in utero substance exposure. Included patients received amantadine for a minimum of 20 days. Mean adjunctive amantadine starting dose was 2.6 mg/(kg·day) and mean discharge dose was 6.7 mg/(kg·day). The treating child and adolescent psychiatrist described five patients as very much improved and three patients as much improved following amantadine therapy. Average seclusions and PRN medications per week were reduced from baseline to week 1 of amantadine (1.81, 95% CI [1.02, 2.61] versus 0.25, 95% CI [0.00, 0.55] (p = 0.01) and 4, 95% CI [2.22, 5.78] versus 1.63, 95% CI [0.71, 2.54] (p = 0.02)), respectively. Both physical restraints and seclusions were reduced from baseline in the second week of amantadine (1.56, 95% CI [0.45, 2.68] versus 0.00, 95% CI [0.00, 0.00] [p = 0.04] and 1.81, 95% CI [1.02, 2.61] versus 0.13, 95% CI [0.00, 0.35] [p = 0.01]), respectively. No adverse events related to amantadine were identified. CONCLUSIONS: We describe clinical improvement supported by objective measures in eight children with aggressive behavior treated with adjunctive amantadine. These findings warrant further investigation as patients were taking other mood stabilizing medications and there are limitations associated with retrospective chart reviews.

Pharmacogenetics of Cytochrome P450 Enzymes in American Indian and Caucasian Children Admitted to a Psychiatric Hospital.

OBJECTIVE: The cytochrome P450 (CYP450) enzyme system metabolizes many psychiatric medications. We compare frequencies of alleles and phenotypes for CYP2D6, CYP2C9, and CYP2C19 in American Indian (AI) and Caucasian youth treated at a psychiatric hospital in the Northwestern United States. METHODS: A retrospective chart review evaluated CYP450 pharmacogenetic (PGx) data from the Shodair Children's Hospital Clinical Genetic Laboratory between 2006 and 2014. CYP2D6 genotyping was performed using the xTAG® CYP2D6 Kit (Luminex, Austin, TX). CYP2C9 and CYP2C19 genotyping was performed by laboratory-developed assays using allele-specific quantitative polymerase chain reaction (qPCR) and/or melt-curve analysis. RESULTS: A total of 123 AIs and 688 Caucasians met criteria for inclusion. The overall prevalence of CYP2D6 poor metabolizers was 8.3% (95% Confidence Interval [CI] 6.1%, 10.4%), 9.3% in Caucasians (95% CI 7.1%, 11.5%), and 2.4% in AIs (95% CI 0%, 5.2%). The overall prevalence of CYP2D6 ultrarapid metabolizers was 1.6% (95% CI 0.7%, 2.5%), 1.6% in the Caucasians (95% CI 0.7%, 2.5%), and 1.6% in AIs (95% CI 0%, 3.9%). The overall prevalence of CYP2C9 poor metabolizers was 3% (95% CI 1.7%, 4.2%), 3.2% in Caucasians (95% CI 1.8%, 4.6%), and 1.8% in AIs (95% CI 0%, 4.2%). The overall prevalence of CYP2C19 poor metabolizers was 2.5% (95% CI 1.3%, 3.6%), 2.9% in Caucasians (95% CI 1.6%, 4.2%), and 0% in AIs. The overall prevalence of CYP2C19 ultrarapid metabolizers was 1.5% (95% CI 0.6%, 2.4%), 1.6% in Caucasians (95% CI 0.6%, 2.6%), and 0.9% in AIs (95% CI 0%, 2.6%). CONCLUSIONS: This study is the first to identify differences in polymorphism frequencies of the CYP450 system in AIs and Caucasian youth admitted to a psychiatric hospital. Our findings warrant further study of these populations to determine if these differences are generalizable to the larger population of Caucasian and AI/Alaska Native youth in the Northwestern United States.