Key PointsQuestionDoes pharmacogenetics-informed (CYP2D6andCYP2C19genotypes) dosing of tricyclic antidepressants result in faster attainment of therapeutic plasma concentrations, higher effectiveness, and fewer and less severe adverse effects compared with usual treatment?FindingsIn this randomized clinical trial of 111 patients with major depressive disorder, dosing based on preemptive pharmacogenetic testing led to faster attainment of therapeutic plasma concentrations and potentially fewer and less severe adverse effects. No effect on depressive symptoms was found.MeaningThese findings indicate that pharmacogenetics-informed dosing of tricyclic antidepressants can be safely applied and contributes to personalized antidepressant treatment.