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.

Trends in vaping and smoking behavior before and during the COVID-19 pandemic in Canada: Beneficial and potentially detrimental changes.

INTRODUCTION: E-cigarette and cigarette use may have changed during the COVID-19 pandemic, however, there is no consensus in existing literature, and current Canadian studies have not used representative samples. Thus, there is a need for robust national estimates. OBJECTIVE AND METHODS: The primary objective was to describe the 30-day period prevalence of smoking and vaping before and during the COVID-19 pandemic in Canada. This study analyzed three years of the cross-sectional Canadian Tobacco and Nicotine Survey: 2019 (pre-pandemic), 2020 (9 months into the pandemic) and 2021 (21 months into pandemic). RESULTS: Thirty-day period prevalence of vaping over the 2019, 2020, and 2021 study periods were 4.8 (95%CI: 4.2-5.3), 4.6% (95%CI: 4.1-5.2), and 5.2% (95%CI: 4.7-5.7), respectively. The 30-day period prevalence of smoking over the 2019, 2020, and 2021 study periods were 11.9% (95%CI: 10.9-12.7), 10.3% (95%CI: 9.4-11.2), and 10.3% (95%CI: 9.4-11.1), respectively. Notably, estimates of smoking for females decreased considerably from 2019 (11.0%; 95%CI: 9.9--12.2%) to 2020 (8.6%; 95%CI: 7.5-9.7). Estimates of vaping in those aged 20-24 increased substantially from 2020 (13.0%; 95%CI: 10.9-15.1) to 2021 (17.2%; 95%CI: 15.4-18.9). CONCLUSIONS: Changes to smoking and vaping were restricted to subsets within the population. In those aged 20-24, there was a modest increase in vaping from 2020 to 2021. In females, there was a decrease in smoking from 2019 to 2020, which persisted in 2021.

Pharmacogenomic Testing and Depressive Symptom Remission: A Systematic Review and Meta-Analysis of Prospective, Controlled Clinical Trials.

Pharmacogenomic (PGx) testing has emerged as a compelling strategy that clinicians can use to inform antidepressant medication selection and dosing, but the clinical efficacy of this strategy has been questioned. We systematically reviewed and meta-analyzed clinical trials for an association between the use of PGx-guided antidepressant therapy and depressive symptom remission in patients with major depressive disorder (MDD). We included prospective, controlled clinical trials published in English up to July 12, 2022. Data extraction and synthesis adhered to the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Each trial was assessed for risk of bias and a random-effects model was used to estimate pooled risk ratios. Thirteen trials comprising 4,767 patients were analyzed, including 10 randomized controlled trials, and three open label trials. Across all included trials, those that received PGx-guided antidepressant therapy (n = 2,395) were 1.41 (95% confidence interval (CI) = 1.15-1.74, P = 0.001) more likely to achieve remission compared with those that received unguided antidepressant therapy (n = 2,372). Pooled risk ratios for randomized controlled trials and open label trials were 1.46 (95% CI: 1.13-1.88) and 1.26 (95% CI = 0.84-1.88), respectively. These results suggest that PGx-guided antidepressant therapy is associated with a modest but significant increase in depressive symptom remission in adults with MDD. Efforts to address the heterogeneity in PGx test composition (i.e., genes and alleles tested) and accompanying prescribing recommendations across trials will likely reduce the uncertainty about the efficacy of PGx-guided antidepressant therapy in the literature.