Metabolizing status of CYP2C19 in response and side effects to medications for depression: Results from a naturalistic study

Major depressive disorder (MDD) is one of the leading causes of disability worldwide. Polymorphisms in cytochrome P450 genes (CYP450) were demonstrated to play a significant role in antidepressant response and side effects, but their effect in real-world clinical practice is poorly known. We determined the metabolic status of CYP2C19 based on the combination of *1, *2, *3 and *17 alleles extracted from genome-wide data in 1239 patients with MDD, pharmacologically treated in a naturalistic setting. Symptom improvement and side effects were assessed using the Montgomery and Asberg Depression Rating Scale and the Udvalg for Kliniske Undersogelse scale, respectively. We tested if symptom improvement, response and side effects were associated with CYP2C19 metabolic status adjusting for potential confounders. We considered patients treated with drugs for depression having CYP2C19 genotyping recommended by guidelines (T1 Drugs); secondarily, with all psychotropic drugs having CYP2C19 as relevant metabolic path (T2 Drugs). In the group treated with T1 drugs ( n = 540), poor metabolizers (PMs) showed higher response and higher symptom improvement compared to normal metabolizers ( p = 0.023 and p = 0.009, respectively), but also higher risk of autonomic and neurological side effects ( p = 0.022 and p = 0.022 respectively). In patients treated with T2 drugs ( n = 801), similar results were found. No associations between metabolizer status and other types of side effects were found (psychic and other side effects). Our study suggests potential advantages of CYP2C19 pharmacogenetic testing to guide treatment prescription, that may not be limited to the drugs currently recommended by guidelines. (c) 2022 Elsevier B.V. and ECNP. All rights reserved.