Effect of CYP2D6 genetic variation on patient-reported symptom improvement and side effects among children and adolescents treated with amphetamines.

OBJECTIVES: Amphetamine-based medications are recommended as a first-line pharmacotherapy for the treatment of attention-deficit/hyperactivity disorder in children and adolescents. However, the efficacy and tolerability of these medications vary across individuals, which could be related to interindividual differences in amphetamine metabolism. This study examined if genotype-predicted phenotypes of the cytochrome P450 isozyme CYP2D6 were associated with self-reported side effects and symptom improvement in youth treated with amphetamines. METHODS: Two hundred fourteen participants aged 6-24 who had a history of past or current amphetamine treatment were enrolled from Western Canada. Amphetamine dose and duration information was collected from the participants along with questions regarding adherence, concomitant medications, symptom improvement and side effects. DNA was extracted from saliva samples and genotyped for CYP2D6 . Binomial logistic regression models were used to determine the effect of CYP2D6 metabolizer phenotype with and without correction for phenoconversion on self-reported symptom improvement and side effects. RESULTS: Genotype-predicted CYP2D6 poor metabolizers had significantly higher odds of reporting symptom improvement when compared to intermediate metabolizers (OR = 3.67, 95% CI = 1.15-11.7, P  = 0.029) after correction for phenoconversion and adjusting for sex, age, dose, duration, and adherence. There was no association between CYP2D6 metabolizer phenotype and self-reported side effects. CONCLUSION: Our findings indicate that phenoconverted and genotype-predicted CYP2D6 poor metabolizer phenotype is significantly associated with higher odds of symptom improvement in children and adolescents treated with amphetamine. If replicated, these results could inform the development of future dosing guidelines for amphetamine treatment in children and adolescents.

Using a Rapid Learning Health System for Stratified Care in Emerging Adult Mental Health Services: Protocol for the Implementation of Patient-Reported Outcome Measures.

BACKGROUND: Mental illness among emerging adults is often difficult to ameliorate due to fluctuating symptoms and heterogeneity. Recently, innovative approaches have been developed to improve mental health care for emerging adults, including (1) implementing patient-reported outcome measures (PROMs) to assess illness severity and inform stratified care to assign emerging adults to a treatment modality commensurate with their level of impairment and (2) implementing a rapid learning health system in which data are continuously collected and analyzed to generate new insights, which are then translated to clinical practice, including collaboration among clients, health care providers, and researchers to co-design and coevaluate assessment and treatment strategies. OBJECTIVE: The aim of the study is to determine the feasibility and acceptability of implementing a rapid learning health system to enable a measurement-based, stratified care treatment strategy for emerging adults. METHODS: This study takes place at a specialty clinic serving emerging adults (age 16-24 years) in Calgary, Canada, and involves extensive collaboration among researchers, providers, and youth. The study design includes six phases: (1) developing a transdiagnostic platform for PROMs, (2) designing an initial stratified care model, (3) combining the implementation of PROMs with stratified care, (4) evaluating outcomes and disseminating results, (5) modification of stratified care based on data derived from PROMs, and (6) spread and scale to new sites. Qualitative and quantitative feedback will be collected from health care providers and youth throughout the implementation process. These data will be analyzed at regular intervals and used to modify the way future services are delivered. The RE-AIM (Reach, Effectiveness, Adoption, Implementation, and Maintenance) framework is used to organize and evaluate implementation according to 3 key objectives: improving treatment selection, reducing average wait time and treatment duration, and increasing the value of services. RESULTS: This project was funded through a program grant running from 2021 to 2026. Ethics approval for this study was received in February 2023. Presently, we have developed a system of PROMs and organized clinical services into strata of care. We will soon begin using PROMs to assign clients to a stratum of care and using feedback from youth and clinicians to understand how to improve experiences and outcomes. CONCLUSIONS: This study has key implications for researchers and clinicians looking to understand how to customize emerging adult mental health services to improve the quality of care and satisfaction with care. This study has significant implications for mental health care systems as part of a movement toward value-based health care. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/51667.

Impact of Cytochrome P450 Genetic Variation on Patient-Reported Symptom Improvement and Side Effects Among Children and Adolescents Treated with Fluoxetine.

Background: Clinical practice guidelines recommend the use of fluoxetine, a selective serotonin reuptake inhibitor (SSRI), as a first-line pharmacotherapy for major depressive disorder (MDD) and obsessive compulsive disorder (OCD) in children and adolescents. However, response and tolerability to fluoxetine varies from child to child, which may in part, be a result of interindividual differences in fluoxetine metabolism. In this study, we examined whether genotype-predicted activity scores of cytochrome P450 enzymes were associated with patient-reported symptom improvement and side effects in children and adolescents treated with fluoxetine. Methods: Ninety children and adolescents aged 7-18 with a MDD or OCD diagnosis and a history of fluoxetine treatment were recruited from Western Canada. For each participant, fluoxetine dose and duration information were collected, as well as questions about adherence, side effects, and symptom improvement. DNA was extracted from a saliva sample and genotyped for CYP2D6, CYP2C19, CYP2C9, CYP3A4, and CYP3A5. Logistic regression models were fitted to assess the impact of activity scores on symptom improvement and side effects. Results: Increased CYP2D6 activity score was significantly associated with reduced odds of symptom improvement (odds ratio [OR] = 0.46, 95% confidence interval [CI] = 0.23-0.91, p = 0.028) as well as a trend association with reduced side effects (OR = 0.49, 95% CI = 0.22-1.07, p = 0.072), after adjusting for age, sex, diagnosis, dose, duration, adherence, and activity scores of the other assessed CYP enzymes. No associations with symptom improvement or side effects were detected for the other CYP enzymes examined. Conclusions: Our results suggest that an increase in the genotype-predicted CYP2D6 activity score was associated with a decrease in the odds of reporting symptom improvement among children and adolescents treated with fluoxetine. These findings will contribute to future updates of pharmacogenetic-based SSRI prescribing guidelines and if replicated, could inform fluoxetine treatment in children and adolescents with MDD or OCD. Clinical Trial Registration: NCT04797364.

A qualitative study on the implementation of a transdiagnostic cognitive behavioral therapy for children in a child welfare residential treatment program.

BACKGROUND: Youth with severe emotional or behavioral issues who are involved with child welfare authorities are sometimes placed in intensive care services in a residential treatment program. Evidence-based psychotherapies are often used in residential treatments, but there is very little research on how to adapt psychotherapy for residential treatment. OBJECTIVE: To describe the implementation of a transdiagnostic cognitive behavioral therapy (the Unified Protocol for Transdiagnostic Treatment of Emotional Disorders in Children) in a residential treatment program for children. PARTICIPANTS AND SETTING: Staff (n = 20) at a residential facility in Calgary, Canada. METHODS: A combination of qualitative interviews and focus groups were conducted before and after therapy to identify barriers and facilitators to implementation. Data were analyzed and reported using the Consolidated Framework for Implementation Research and the Framework for Reporting Adaptations and Modifications to Evidence-based Implementation Strategies. RESULTS: Modifications were made to the program including creating inclusive language, integrating relevant content targeting pediatric irritability, delivering sessions online for caregivers, and using additional staff to support youth to learn and practice the application of the content and behavioral interventions. Key barriers to implementation of the Unified Protocol included staff turnover and the difficulty of sustaining a critical mass of knowledge surrounding the Unified Protocol. The major facilitators to implementation were the perceived quality of the program and advantages of the program to children and their caregivers. CONCLUSIONS: This study supports the feasibility and acceptability of providing transdiagnostic cognitive behavioral therapies for children in residential treatment and provides a template for how to implement evidence-based practice in residential treatment.