Dose–Concentration Relationship and Clinical Outcomes of Duloxetine in Generalized Anxiety Disorder

<b>Background/Objectives</b>: This study aimed to investigate plasma duloxetine concentrations, factors influencing these concentrations, and the relationship between plasma levels and clinical response in patients diagnosed with generalized anxiety disorder who were treated with duloxetine. Additionally, the study evaluated whether dose escalation resulted in proportional increases in plasma concentration and assessed the clinical utility of therapeutic drug monitoring (TDM) for duloxetine. <b>Methods</b>: In this study, plasma duloxetine levels were analyzed in 68 patients with generalized anxiety disorder who had been receiving duloxetine treatment for at least three months. A review of digital medical files revealed that duloxetine was initiated at 30 mg/day in all patients, and doses were increased to 60 or 90 mg/day in those with insufficient symptom improvement. Digital medical files indicated that participants had been on the final prescribed duloxetine dose for at least four weeks at the time of plasma level measurement. Baseline Hamilton Anxiety Rating Scale (HAM-A) and Generalized Anxiety Disorder-7 (GAD-7) scores were compared with scores obtained on the day of blood sampling. Plasma duloxetine concentrations were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Associations between dose, plasma concentration, and clinical response were statistically analyzed. <b>Results</b>: Plasma duloxetine concentrations increased significantly following dose escalation. However, no significant correlation was observed between plasma concentrations and percentage change in HAM-A scores. Although patients receiving 60 or 90 mg/day had higher plasma levels than those maintained on 30 mg/day, clinical improvement did not differ significantly between dose groups. In addition to dose, increasing age and non-smoking status were associated with higher plasma duloxetine concentrations. <b>Conclusions</b>: Duloxetine demonstrates a predictable dose-concentration relationship; however, in this response-guided titration setting, plasma concentrations were not consistently associated with clinical improvement. Accordingly, these findings suggest that routine therapeutic drug monitoring may not consistently predict clinical response to duloxetine in generalized anxiety disorder; nevertheless, considering the study's limitations, it could still offer clinically relevant insights in selected pharmacokinetically sensitive or treatment-resistant cases.