365. Association between CYP2D6 genotype and treatment outcomes in hospitalized patients with major depressive disorder: a retrospective cohort study

Abstract

Abstract Background Cytochrome P450 2D6 (CYP2D6) is a highly polymorphic hepatic enzyme involved in the metabolism of many commonly prescribed antidepressants. Genetic variations in CYP2D6 leads to differences in drug metabolism, affecting plasma concentrations and potentially influencing treatment effectiveness and tolerability. Although CYP2D6 genotyping is a potentially useful tool for personalizing antidepressant treatment, results focused on characterization of this pharmacogenetic association are still inconsistent. Consequently, discrepancies between sources of antidepressant dosing guidelines based on CYP2D6 genotype are substantial, and preemptive CYP2D6 genotyping is often not performed in the clinical setting. Aims & Objectives To investigate the association between CYP2D6 metabolizer status and the effectiveness and tolerability of antidepressant treatment in hospitalized patients diagnosed with major depressive disorder (MDD). Method This retrospective observational study included 99 adults (aged 18 to 65 years) diagnosed with MDD and hospitalized at the Military Medical Academy in Belgrade, Serbia. All received stable antidepressant monotherapy or antidepressant dual therapy and were examined at baseline, after two weeks and at discharge (usually 4–6 weeks later). The severity of depression was assessed using the Hamilton Depression Rating Scale (HAM-D) and the Beck Depression Inventory-II (BDI-II). Adverse drug reactions (ADRs) were assessed using the Toronto Side Effects Scale (TSES). CYP2D6 genotyping was performed retrospectively using TaqMan real-time PCR assays, and patients were categorized into normal (NMs, n = 64), intermediate (IMs, n = 30), and poor metabolizers (PMs, n = 5). Statistical analyzes included ANOVA, Kruskal–Wallis and Fisher’s exact tests. Changes in depressive symptoms were analyzed using ANOVA and ANCOVA with repeated measures, adjusting for age, sex, baseline diagnosis, and episode duration. Results Compared to NMs, IMs and PMs showed lower reductions in HAM-D scores (29% for IMs, p < 0.001; 57% for PMs, p < 0.001) and BDI-II scores (32% for IMs, p < 0.001; 46% for PMs, p < 0.001). Response rates (defined as a reduction in HAM-D score of ≥50) were 64.1% for NMs, 30.0% for IMs (p < 0.001 vs. NMs) and 20.0% for PMs (p = 0.015 vs. NMs). The intensity of ADRs was significantly higher in IMs (3.1 [IQR: 2.1–3.9], p = 0.007) and PMs (4.6 [3.3–5.3], p = 0.002) than in NMs (2.3 [1.8–3.1]). CNS-related adverse events were also more pronounced in IMs (2.5 [1.8–3.2], p = 0.001) and PMs (3.2 [2.6–4.8], p = 0.004) than in NMs (1.9 [1.5–2.2]). Gastrointestinal symptoms showed a similar pattern: IMs (2.0 [1.5–2.8], p = 0.008) and PMs (2.9 [2.4–3.4], p = 0.002) had significantly higher scores than NMs (1.6 [1.3–2.1]). All differences remained significant after FDR adjustment. Discussion & Conclusions CYP2D6 genotype was associated with significant differences in treatment outcomes in hospitalized patients with MDD; specifically, reduced CYP2D6 metabolic activity was associated with poorer antidepressant effectiveness and tolerability. These findings support the potential clinical utility of preemptive CYP2D6 genotyping to identify patients with reduced CYP2D6 metabolic capacity prior to initiation of antidepressant treatment, which could improve treatment personalization and increase the success of antidepressant treatment in individuals with MDD.