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The Influence of CYP2D6 and CYP2C19 Genetic Variation on Diabetes Mellitus Risk in People Taking Antidepressants and Antipsychotics.

ABSTRACT: CYP2D6 and CYP2C19 enzymes are essential in the metabolism of antidepressants and antipsychotics. Genetic variation in these genes may increase risk of adverse drug reactions. Antidepressants and antipsychotics have previously been associated with risk of diabetes. We examined whether individual genetic differences in CYP2D6 and CYP2C19 contribute to these effects. We identified 31,579 individuals taking antidepressants and 2699 taking antipsychotics within UK Biobank. Participants were classified as poor, intermediate, or normal metabolizers of CYP2D6, and as poor, intermediate, normal, rapid, or ultra-rapid metabolizers of CYP2C19. Risk of diabetes mellitus represented by HbA1c level was examined in relation to the metabolic phenotypes. CYP2D6 poor metabolizers taking paroxetine had higher Hb1Ac than normal metabolizers (mean difference: 2.29 mmol/mol; p < 0.001). Among participants with diabetes who were taking venlafaxine, CYP2D6 poor metabolizers had higher HbA1c levels compared to normal metabolizers (mean differences: 10.15 mmol/mol; p < 0.001. Among participants with diabetes who were taking fluoxetine, CYP2D6 intermediate metabolizers and decreased HbA1c, compared to normal metabolizers (mean difference -7.74 mmol/mol; p = 0.017). We did not observe any relationship between CYP2D6 or CYP2C19 metabolic status and HbA1c levels in participants taking antipsychotic medication. Our results indicate that the impact of genetic variation in CYP2D6 differs depending on diabetes status. Although our findings support existing clinical guidelines, further research is essential to inform pharmacogenetic testing for people taking antidepressants and antipsychotics.

SUBMITTER: Austin-Zimmerman I

PROVIDER: S-EPMC8620997 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: The clinical impact of the functional CYP2C19 and CYP2D6 gene variants on antidepressant treatment in people with depression is not well studied. Here, we evaluate the utility of pharmacogenetic (PGx) testing in psychiatry by investigating the association between the phenotype status of the cytochrome P450 (CYP) 2C19/2D6 enzymes and the one-year risks of clinical outcomes in patients with depression with incident new-use of (es)citalopram, sertraline, or fluoxetine. Methods: This study is a population-based cohort study of 17,297 individuals who were born between 1981 and 2005 with a depression diagnosis between 1996 and 2012. Using array-based single-nucleotide-polymorphism genotype data, the individuals were categorized according to their metabolizing status of CYP2C19/CYP2D6 as normal (NM, reference group), ultra-rapid- (UM), rapid- (RM), intermediate- (IM), or poor-metabolizer (PM). The outcomes were treatment switching or discontinuation, psychiatric emergency department contacts, and suicide attempt/self-harm. By using Poisson regression analyses, we have estimated the incidence rate ratios (IRR) with 95% confidence intervals (95% CI) that were adjusted for covariates and potential confounders, by age groups (<18 (children and adolescents), 19−25 (young adults), and 26+ years (adults)), comparing the outcomes in individuals with NM status (reference) versus the mutant metabolizer status. For statistically significant outcomes, we have calculated the number needed to treat (NNT) and the number needed to genotype (NNG) in order to prevent one outcome. Results: The children and adolescents who were using (es)citalopram with CYP2C19 PM status had increased risks of switching (IRR = 1.64 [95% CI: 1.10−2.43]) and suicide attempt/self-harm (IRR = 2.67 [95% CI; 1.57−4.52]). The young adults with CYP2C19 PM status who were using sertraline had an increased risk of switching (IRR = 2.06 [95% CI; 1.03−4.11]). The young adults with CYP2D6 PM status who were using fluoxetine had an increased risk of emergency department contacts (IRR = 3.28 [95% CI; 1.11−9.63]). No significant associations were detected in the adults. The NNG for preventing one suicide attempt/suicide in the children who were using (es)citalopram was 463, and the NNT was 11. Conclusion: The CYP2C19 and CYP2D6 PM phenotype statuses were associated with outcomes in children, adolescents, and young adults with depression with incident new-use of (es)citalopram, sertraline, or fluoxetine, therefore indicating the utility of PGx testing, particularly in younger people, for PGx-guided antidepressant treatment.

Project description:Objectives: To assess the use of three commonly prescribed psychotropic medications in youth placed in residential care (RC). Methods: Participants were youth aged 0-20 years placed in RC institutions at least once during 2016. Data on filled prescriptions were taken from the Norwegian Prescription Database to compare the use of antidepressants, antipsychotics, and stimulants in RC with the age- and gender-adjusted general child population (GenPop) and how this co-varied with reasons for RC placement, age, and gender. Results: One thousand eight hundred fifty-six children and adolescents were identified in RC, with mean age 14 (range 0-20 years), 46% girls, 81% ≥ 13 years. Among those, 423 or 23% used any of the 3 psychotropics, which was significantly more than the 3.7% in GenPop. The prevalence ratios RC/GenPop were 6.6 for antidepressants, 17.9 for antipsychotics, and 4.4 for stimulants. The median number of days per year for the dispensed defined daily doses varied from 8.3 to 244.0 for the different antipsychotics, indicating short time use for most of the people. Polypharmacy was not frequent in RC, as only 26% used ≥2 classes of medication, but still significantly more frequent than the 10% in GenPop. Youth placed in RC for serious behavior problems had significantly higher use of stimulants than those with other placement reasons. Psychotropics were not used below age 6 years, and although the use of antidepressants and antipsychotics overall increased with age, stimulants were mostly used by 6-16-year olds. The girl/boy ratio for any psychotropic medication use in RC was 1.4 (95% confidence interval [95% CI]: 1.1-1.6), significantly higher than the corresponding ratio in GenPop: 1.0 (95% CI: 0.9-1.0). Conclusion: The present findings do not necessarily suggest an overtreatment with medication in RC. However, the frequent short-term use of antipsychotics, presumably for non-psychotic symptoms, is a concern, as it may reflect that the youth are not provided with the recommended first-line psychological treatments.

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The Influence of CYP2D6 and CYP2C19 Genetic Variation on Diabetes Mellitus Risk in People Taking Antidepressants and Antipsychotics.

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