Study protocol for an observational trial: Investigating pharmacogenetic impact on depression treatment using various sequencing and array methods (PharmGen-TRD Study)

Antidepressant metabolism varies widely due to polymorphic cytochrome P450 (CYP) enzymeslike CYP2D6 and CYP2C19, of which various genetic variants exist. These variants influence serum concentrations, leading to side effects, low remission rates, and insufficient responses. Thus, physicians often try multiple antidepressants within a short period, causing increased psychological distress and negatively affecting disease progression. Pharmacogenetic information can be used for more targeted prescriptions. This monocentric observational study at the University Hospital Frankfurt (April 2025-June 2026) will recruit 200 patients with depression and aims to analyze the impact of different genotypes on treatment outcomes. Following genotyping, patients will be classified as normal or non-normal metabolizers and as having actionable or non-actionable genotypes. Clinical parameters, including the number and duration of depressive episodes, antidepressants used, sick leave days, and standardized clinical scores, will be recorded at admission. The study’s primary endpoint is antidepressant discontinuation. Reasons for discontinuation and other treatment interventions will be correlated with patients' genotypes for CYP2D6, CYP2C19, CYP2B6, and other genes. In the experimental part of the study, Oxford Nanopore long-read sequencing will be further investigated and validated. Changes in gut microbiome composition and metabolism will be analyzed during treatment in relation to CYP status and antidepressant use.