Pharmacogenetic profiling via genome sequencing in children with medical complexity.

BACKGROUND: Children with medical complexity (CMC) are a priority pediatric population, with high resource use and associated costs. Genome-wide sequencing is increasingly organized for CMC early in life as a diagnostic test. Polypharmacy becomes common as CMC age. Clinically relevant pharmacogenetic (PGx) information can be extracted from existing genome sequencing (GS) data via GS-PGx profiling. The role of GS-PGx profiling in the CMC population is unclear. METHODS: Prescribed medications were extracted from care plans of 802 eligible CMC enrolled in a structured Complex Care Program over a 10-year period. Drug-gene associations were annotated using curated Clinical Pharmacogenetics Implementation Consortium data. GS-PGx profiling was then performed for a subset of 50 CMC. RESULTS: Overall, 546 CMC (68%) were prescribed at least one medication with an established PGx association. In the GS-PGx subgroup, 24 (48%) carried variants in pharmacogenes with drug-gene guidelines for one or more of their current medications. All had findings of potential relevance to some medications, including 32 (64%) with variants in CYP2C19 that could affect their metabolism of proton-pump inhibitors. CONCLUSION: GS-PGx profiling at the time of diagnostics-focused genetic testing could be an efficient way to incorporate precision prescribing practices into the lifelong care of CMC. IMPACT: Polypharmacy and genetic test utilization are both common in children with medical complexity. The role of repurposing genome sequencing data for pharmacogenetic profiling in children with medical complexity was previously unclear. We identified a high rate of medication use with clinically relevant drug-gene associations in this priority pediatric population and demonstrated that relevant pharmacogenetic information can be extracted from their existing genome sequencing data. Pharmacogenetic profiling at the time of diagnostics-focused genetic testing could be an efficient way to incorporate precision prescribing practices into the lifelong care of children with medical complexity.

The Effect of Melatonin on Benzodiazepine Discontinuation and Sleep Quality in Adults Attempting to Discontinue Benzodiazepines: A Systematic Review and Meta-Analysis.

BACKGROUND: Abrupt discontinuation of benzodiazepines often results in side effects including anxiety and insomnia, which can be barriers to discontinuation among long-term users. Melatonin improves the onset, duration, and quality of sleep. By preventing insomnia in those attempting to discontinue benzodiazepines, melatonin may facilitate benzodiazepine discontinuation. OBJECTIVES: The primary objective was to determine the effect of melatonin compared with placebo on benzodiazepine discontinuation in adults attempting to discontinue benzodiazepines. The secondary objective was to determine the effect of melatonin on sleep quality in this population. METHODS: We searched PubMed, MEDLINE, EMBASE, PsychINFO, and ClinicalTrials.gov from inception to November 2014. We included randomized controlled trials published in English comparing melatonin with placebo that reported benzodiazepine discontinuation or sleep quality. Two reviewers independently screened trials, extracted data, and assessed the risk of bias. RESULTS: We included six trials randomizing 322 participants. The mean age of participants was approximately 64 years. The trials used varied tapering strategies to discontinue benzodiazepines over 4-10 weeks while using melatonin. Melatonin had no effect on the odds of successfully discontinuing benzodiazepines (odds ratio 0.72, 95% confidence interval 0.21-2.41, p = 0.59). There was important heterogeneity among the trials (I (2) = 76%). The effect of melatonin on sleep quality was inconsistent. CONCLUSIONS: Melatonin had no effect on benzodiazepine discontinuation while the effect of melatonin on sleep quality was inconsistent. We cannot rule out a role of melatonin in improving benzodiazepine discontinuation or sleep quality owing to imprecise effect estimates. Larger, well-designed, and reported randomized controlled trials may provide more valid and precise estimates of the effect of melatonin on these outcomes.