Vortioxetine, a multimodal antidepressant, blocks SERT and has a strong affinity for 4 serotonergic receptors. It is an antagonist of the 5-HT3 and 5-HT7 receptors, a partial agonist of 5-HT1B, and an agonist of 5-HT1A. This combined effect on SERT and serotonergic receptors increases the postsynaptic extracellular concentration of serotonin, dopamine, and noradrenaline.75

In 12 short-term (6-8 weeks) clinical trials comparing vortioxetine to placebo for the treatment of depression in adults, 8 demonstrated positive results, as measured by MADRS or HAM-D, while 3 studies showed no significant difference vs placebo and 1 study failed.75 Onset of action was noted within 2 weeks for patients receiving 10 mg/day and within 1 week for patients receiving 20 mg/day, with maximum response near 4 weeks.75 It has been suggested that the failed trial was due to neither vortioxetine nor the active comparator, duloxetine, demonstrating superiority to placebo.75

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Two long-term studies have been conducted with vortioxetine. In the first study by Boulenger et al, 639 subjects received open-label vortioxetine (5-10 mg/day) for 12 weeks. Patients in remission were randomized to receive vortioxetine or placebo. 

The relapse rate was significantly lower for patients receiving vortioxetine (13% vs 26%; P=.0035).75,76 The second study was a 52-week open-label extension study of vortioxetine (2.5-10 mg/day) among 535 patients who had completed an 8-week lead-in study (vortioxetine 5 mg/day). The relapse rate among patients in remission at the start of the study was 9.7%. In addition, in the overall population, responders increased from 63% to 94% and remission from 42% to 83%.75,77 Given that this was an open-label study, the conclusions drawn are limited by the lack of a placebo control.77

The CONNECT study was designed to assess the effect of vortioxetine on cognitive function. CONNECT enrolled 602 adult patients with MDD and randomized subjects to receive 8 weeks of treatment with vortioxetine (10-20 mg/day), duloxetine (60 mg/day), or placebo.78

Vortioxetine demonstrated statistical superiority to placebo on the primary endpoint, the Digit Symbol Substitution Test (DSST).78 Additional and secondary endpoint measures, which included the patient-reported Perceived Deficits Questionnaire (PDQ), the Clinical Global Impressions-Global Improvement Scale (CGI-I), and the MADRS, also demonstrated significant separation from placebo. Duloxetine did not demonstrate a statistically significant difference from placebo on the DSST, but was statistically different on endpoint measures on the PDQ, MADRS, and CGI-I.78

Among the limitations of this study is a lack of formalized diagnostic inclusion criteria for cognitive dysfunction in patients with MDD. The study included patients with self-reported cognitive dysfunction (vs objectively assessed cognitive dysfunction), and therefore may have resulted in inclusion of those without clinically relevant cognitive dysfunction. In addition, this study was only powered to detect statistical differences between vortioxetine and placebo on the primary endpoint, the DSST, limiting the ability to detect statistically significant differences between vortioxetine and duloxetine on any other primary or secondary endpoint measures.78

A second study (FOCUS) enrolled 598 subjects and reported statistically significant improvement in cognitive function, including executive functioning, attention, speed of processing, and memory with vortioxetine (10 or 20 mg/day) vs placebo (Figure 4).52 These effects were independent of the effect of vortioxetine on improving depressive symptoms.52 It should be noted that vortioxetine is not FDA-approved for treatment of cognitive impairment. 

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New agents at-a-glance

Table 4 describes the key characteristics of newly approved antidepressants.

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