1. In this retrospective cohort study, in patients prescribed citalopram, poor/intermediate CYP2C19 metabolizers experienced significantly greater weight gain at 6 months after starting citalopram when compared to normal and rapid/ultrarapid metabolizers.

Evidence Rating Level: 2 (Good)

Obesity and depression are closely related such that patients with obesity have a 55% increased risk of being diagnosed with depression, and patients with depression have a 58% increased risk of developing obesity. Unfortunately, a side effect of selective serotonin reuptake inhibitors, which is the first-line treatment for depression, includes weight gain. Genetic variations between individuals is a factor that can alter the medication’s efficacy, in particular variation of the cytochrome P450 (CYP) enzymes. Interestingly, dosing guidelines have been developed for certain metabolizer phenotypes. Previous research has found an association between genetic variants of obesity and treatment response of SSRIs in depression, but further investigation into pharmacogenomics and weight gain is warranted. This retrospective cohort study aims to study the association between metabolizer phenotype and weight gain in patients prescribed with SSRIs. 663 patients were included in the final analysis, which included patients from the Right Drug, Right Dose, Right Time (RIGHT) Study recruited from 2004 to 2018 who previously underwent genetic sequencing. The three CYP enzymes that were studied were CYP2C19, CYP2D6, and CYP2C9, and patients were categorized into poor/intermediate, normal, and rapid/ultrarapid metabolizers. The total body weight gain percentage (TBWG%) at 6 months for patients who were prescribed an SSRI was 0.7%; TBWG% for citalopram was 1.1%, 0.9% for paroxetine, 1.1% for sertraline, and 0.1% for fluoxetine. With respect to CYP enzyme metabolizer status, patients prescribed citalopram who were poor/intermediate CYP2C19 metabolizers gained significantly more weight than normal and rapid/ultrarapid metabolizers (P=.0001). Otherwise, for fluoxetine. paroxetine, and sertraline there was no significant difference in TBWG% when comparing between CYP2D6 metabolizer phenotypes. There was also no significant difference for fluoxetine and sertraline with the CYP2C19 phenotype, and for fluoxetine with the CYP2D6 phenotype. With respect to the effect of metabolizers on TWBG%, poor CYP2C19 metabolizers on citalopram experienced significantly greater weight gain than rapid metabolizers. Otherwise, for the CYP2D6 phenotype, there was no significant effect for paroxetine, fluoxetine, and sertraline. For the CYP2C9 phenotype, there was no significant difference for fluoxetine, and for the CYP2C19 phenotype, there was no significant difference for fluoxetine and sertraline. Overall, 6 months after prescribing citalopram, patients with a poor/intermediate metabolizer status of CYP2C19 experienced 1.7% more weight gain than normal metabolizers. These findings may have a role in guiding future management decisions surrounding the choice of first-line SSRI in patients with certain risk factors, and demonstrates the importance of pharmacogenomics, especially when considering adverse effects. A major limitation of this study is the small sample size for certain metabolizer phenotypes, which may cause type II error when analyzing outcomes.

Click to read the study in BMC Medicine

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