Therapeutic reference range for duloxetine in the treatment of depression revised: A systematic review and meta-analysis.

The concentration-effect relationship for the serotonin and norepinephrine reuptake inhibitor duloxetine forms the basis of its therapeutic concentration reference range. However, it lacks systematic investigation and the range reported in the present therapeutic drug monitoring guidelines can only be considered preliminary. A systematic review and meta-analysis were conducted in four databases to determine the optimal target concentration for duloxetine's antidepressant effects and to identify factors that influence its blood concentrations. Relevant articles reporting duloxetine blood concentrations in relation to i) clinical effects/adverse effects, ii) pharmacokinetics and iii) receptor occupancy were analyzed. Out of 340 articles, 11 studies were selected for qualitative synthesis, with seven being included in the quantitative analysis. Three studies showed a positive correlation between duloxetine blood concentrations and antidepressant effects. The adverse event irritability/anxiety was found to be concentration-dependent in one study. Across four studies (n = 223), the 25%-75% interquartile concentration range was 22-72 ng/mL. Two studies reported interquartile ranges of responders (72-116 ng/mL and 65-123 ng/mL), with one of them identifying a threshold concentration for clinical response (58 ng/mL). Neuroimaging studies indicated that 80% serotonin transporter occupancy is reached with blood concentrations above 10-15 ng/mL, while 50% norepinephrine transporter occupancy is observed at 58 ng/mL. We suggest a therapeutic reference range between 20 and 120 ng/mL to achieve optimal antidepressant effects during duloxetine treatment in adults. Due to duloxetine's inhibition of both serotonin and norepinephrine receptors, some patients benefit from low duloxetine concentrations, while others may need higher concentrations to benefit from norepinephrine transporter blockage. In case of non-response at low to medium concentrations (i.e. < 60 ng/mL), we recommend dose titration within the proposed reference range. Blood concentrations can be affected by smoking and certain medications. Hence, therapeutic drug monitoring of duloxetine is strongly recommended for dose titration, particularly with initial prescription.