@conference{
author = "Joković, Danilo and Milosavljević, Filip and Stojanović, Zvezdana and Šupić, Gordana and Vojvodić, Danilo and Jukić, Marin and Uzelac, Bojana and Petković-Ćurčić, Aleksandra",
year = "2022",
abstract = "Introduction: Available antidepressants are not always effective and the discovery of new antidepressants is slow. Since most antidepressants are metabolized by polymorphic CYP450 liver enzymes, it has been hypothesized that personalized dosing that takes into the account genotype-predicted CYP450 enzyme capacity may improve their effectiveness [1]. Even though it is well known that CYP450 polymorphism impacts plasma levels of many antidepressants [2,3], available evidence on the impact of CYP450 polymorphism on antidepressant efficacy and tolerability is insufficiently strong and often conflicting.
Aim: The aim of this study was to test if CYP2C19 genotype influences efficacy and tolerability of antidepressant therapy in the cohort of 102 inpatients.
Methods: The study was performed at the Military Medical Academy in Belgrade, Serbia. Patients hospitalized for depression and treated with at least one antidepressant were included if they signed the informed consent form. Patients were monitored at the hospital admission and after two and four weeks of follow-up. The drug efficacy was measured with HAM-D (Hamilton depression rating) scale, while tolerability was monitored by TSES (Toronto Side-effects scale) [4]. Patients were retrospectively genotyped for CYP2C19 after the study completion and subsequently categorized as Slow (SM), Normal (NM), or Fast metabolizers (FM). Differences between CYP2C19 metabolizer groups at week four were compared with ANCOVA for HAM-D score, Kruskal-Wallis test for TSES and binary-logistic regression for response rate. Individual adverse reactions were analysed with post-hoc Man-Whitney test.
Results: In total, 102 patients were included; 41 were NM controls, 24 were SM and 37 were RM. Most commonly prescribed primary antidepressants were escitalopram (n=20), trazodone (n=14), mirtazapine (n=12), sertraline (n=12) and venlafaxine (n=10). The fluoxetine-equivalent doses were the not different across groups (p>0.1). While all categories experienced significant reduction in HAMD score during 4 weeks, compared with NMs, the reduction was 36% ([CI95%: 20% - 52%], p<0.0001) less pronounced among SMs. Similarly, response rate was 75% lower in SMs compared with NMs (NM: 34/41 vs SM: 5/24, p<0.0001); response was defined as ≥50% reduction in HAMD score [5]. Finally, SM patients had higher median intensity scores than NMs at week 4 (NM median: 2.5 [IQR: 2.0 - 3.2] vs SM median: 3.2 [IQR: 2.8 - 3.7]; p=0.021, q=0.042). Post hoc analysis revealed that increased burden of nervousness, agitation, and dyspepsia contributed the most to the worse tolerability in SMs. There were no significant differences between FM and NM patients in any of the measured outcomes.
Conclusions: This study revealed that, in the cohort of inpatients treated with heterogeneous antidepressants, the reduced CYP2C19 metabolic capacity is associated with worse therapy efficacy and tolerability, whereas the increased CYP2C19 metabolic capacity is not. Therefore, it is likely that SM group does not receive the appropriate treatment under standard psychiatric practice, which is in most cases unaware of the patients’ CYP2C19 genotype. Even though this study does not have sufficient power for an unequivocal conclusion related to the need of pre-emptive CYP2C19 genotyping of antidepressant treated patients, it contributes to the body of already existing evidence on the clinical usefulness of CYP2C19 genotyping in psychiatry.",
publisher = "Elsevier",
journal = "Neuroscience Applied",
title = "CYP2C19 slow metabolizer phenotype is associated with lower antidepressant efficacy and tolerability: clinical study on 102 inpatients",
volume = "1",
number = "Supplement 2",
pages = "54-55",
doi = "10.1016/j.nsa.2022.100217"
}
