A randomized, double-blind, study of vortioxetine versus agomelatine in adults with major depressive disorder (MDD) switched after inadequate response to SSRI or SNRI treatment

BACKGROUND: The investigational antidepressant vortioxetine (Lu AA21004) is a multimodal 5-HT3, 5- HT7 and 5-HT1D receptor antagonist, 5-HT1B receptor partial agonist, 5-HT1A receptor agonist and inhibitor of the 5-HT transporter [1]. Data from randomized trials comparing treatment strategies in patients who were unresponsive to first-line antidepressant treatment are limited. In the large open-label STAR*D study in which patients received treatment with citalopram (level 1) and non-responders were randomly switched to a second treatment (level 2), the mean remission rate after 12-14 weeks was 30.6% [2]. OBJECTIVES: To compare efficacy and tolerability of flexible-dose treatment with vortioxetine versus agomelatine in patients with MDD who presented with an inadequate response to SSRI/SNRI monotherapy and wanted to switch treatment and would benefit, in the investigator’s clinical opinion.Methods: Randomized, double-blind comparator study (NCT01488071). Primary efficacy endpoint was the change from baseline to Week 8 in MADRS total score in the full-analysis set (FAS) analysed by MMRM using a non-inferiority test. Secondary endpoints included assessment of remission (MADRS total score ≤10), anxiety symptoms (HAM-A), global clinical judgment (CGI), and overall functioning (SDS). RESULTS: Eligible patients were randomized (1:1) to vortioxetine (10-20mg/day) or agomelatine (25-50 mg/day) for 12 weeks of double-blind treatment. On the primary efficacy endpoint, vortioxetine (n=252) was statistically significantly superior to agomelatine (n=241) (p<0.05) by 2.2 MADRS points. Significant differences in favour of vortioxetine were found for the MADRS, HAM-A, CGI-S, CGI-I, and SDS from Week 4 onwards (FAS, MMRM; p<0.05) and robustness was confirmed by significant differences by ANCOVA (FAS, LOCF). Remission rates for vortioxetine versus agomelatine (LOCF) were 40.5% versus 29.5% (p=0.0054) at Week 8 and 55.2% versus 39.4% (p=0.0002) at Week 12. Fewer patients withdrew due to adverse events with vortioxetine (5.9%) than agomelatine (9.5%). Adverse events with the highest incidence were nausea, headache, dizziness and somnolence. CONCLUSIONS: The primary efficacy endpoint of this comparator study was met, with vortioxetine also showing a significant benefit compared to agomelatine in difficult to treat MDD patients who directly switched antidepressant treatment after an inadequate response to SSRI/SNRI treatment. Statistically significant differences were seen from Week 4 onwards. The vortioxetine remission rate after 8 and 12 weeks was higher than in the STAR*D study. Thus, vortioxetine was both efficacious and well-tolerated. [1] Bang-Andersen B, et al. J Med Chem 2011;54:3206-21. [2] Rush AJ, et al. Am J Psychiatry 2006;163:1905-17. LEARNING OBJECTIVES:  At the conclusion of this session, the participant should understand that in MDD patients with an inadequate response to SSRI/SNRI treatment, subsequent switch to either vortioxetine or agomelatine resulted in clinically relevant improvement after 8 to 12 weeks of treatment.  In this difficult to treat patient group, vortioxetine showed a significant benefit versus agomelatine on the primary efficacy endpoint and on most secondary efficacy endpoints as early as Week 4.