Purpose Depression is one of the leading causes of avoidable suffering worldwide, and over 50% of patients do not respond to their first antidepressant treatment, which underscores the need for more effective alternatives. This clinical predicament urgently requires an effective solution. The core objective of this study is to clarify the clinical efficacy and application value of the triple reuptake inhibitor toludesvenlafaxine in patients with poor response to the first antidepressant therapy, providing a new basis for treatment options for this refractory group. Methods This multicenter study included 61 patients meeting Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition ( DSM-V ) criteria for depression. All patients still had a Montgomery Depression Rating Scale (MADRS) score of ≥24 after 4 weeks of treatment with an adequate single initial antidepressant, and were clearly classified as an ineffective or partially effective initial antidepressant treatment. Patients were switched to toludesvenlafaxine for an 8-week treatment period. The primary outcome measure was the change in MADRS score from baseline to 8 weeks. The secondary outcome measures included the changes in the scores of the Hamilton Anxiety Scale (HAMA), the Dimensional Anhedonia Rating Scale (DARS), the Quality of Life Enjoyment and Satisfaction Questionnaire, Short Form (Q-LES-Q-SF), and the Clinical Global Impression of Severity Scale (CGI-S) from baseline to 8 weeks. Results For such patients that did not respond to the first treatment, significant and rapid efficacy was demonstrated after switching to toludesvenlafaxine. At 8 weeks of treatment, the average MADRS score of the patients decreased by 15.5 points compared with the baseline (95% CI, −17.7 to −13.3; p 0.0001; Cohen’s d = 2.35). Forty-three percent of them met the clinical remission, and 67% achieved a clinical response. More clinically significant is that the therapeutic effect emerged at an early stage—2 weeks (95% CI, −9.4 to −6.4; p 0.0001; Cohen’s d = 1.52) and 4 weeks (95% CI, −13.3 to −9.8; p 0.0001; Cohen’s d = 2.11). After 2 weeks of treatment, there were statistically significant differences in the HAMA, Q-LES-Q-SF, and CGI-S scores at each time point compared with the baseline. The improvement in the DARS score was statistically significant from 4 weeks. In terms of safety, the most common adverse reactions were palpitations, constipation, nausea, vomiting, hypoesthesia, and dizziness, which are mostly mild to moderate and controllable. In particular, the drug significantly improved sexual dysfunction (95% CI, −4.3 to −0.7; p = 0.0071), which is crucial for improving treatment compliance. Conclusion This study confirmed that toludesvenlafaxine not only has significant clinical efficacy (including early onset, high remission, and response) for patients with depression who did not respond to the first antidepressant treatment, but also has good safety and can improve sexual dysfunction that affects compliance. This result highlights the significant position of toludesvenlafaxine in addressing the key clinical challenge of first treatment failure, providing a highly valuable new option for the subsequent treatment of such patients.
Yang et al. (2026) studied this question.