Head-to-Head Comparison of Vortioxetine Versus Desvenalfaxine in Patients With Depression and Partial Response to SSRIs


Researchers performed a head-to-head trial of vortioxetine versus desvenalfaxine in patients with depression and partial response to SSRIs.




“Mr Sheff” is a 29-year-old African American male with a history of moderate, single-episode major depressive disorder (MDD). He did not respond to a trial of bupropion. He is currently maintained on citalopram monotherapy (40 mg daily) for the past 12 weeks, to which he has had a partial response. He previously declined a referral for cognitive-behavioral therapy.

At his most recent outpatient clinic visit, he inquired about a trial of a medication with a different mechanism of action than citalopram, including serotonin-norepinephrine reuptake inhibitors (SNRIs) and vortioxetine. As his psychiatrist, how would you respond?

Approximately half of patients with MDD are non- or partial responders to treatment with selective serotonin reuptake inhibitors (SSRIs).1 Partial response and residual symptoms of depression are negatively associated with illness course and outcomes.2

Clinical guidelines recommend switching to a different class of antidepressant in cases of non- and partial response. SSRIs are generally first-line treatments, and SNRIs are generally second-line treatments for MDD.3

Vortioxetine is a multimodal antidepressant that modulates the activity of serotonin and other neurotransmitter systems.4 Although head-to-head studies of antidepressants are rare, there is some evidence of superior efficacy of vortioxetine over SNRIs, including extended-release venlafaxine5 and duloxetine.6

The Current Study

The VIVRE study was an international, double-blind, phase 4 randomized controlled trial of vortioxetine versus desvenlafaxine on depressive symptoms, overall functioning, and health-related quality of life in patients with MDD and partial response to SSRIs.7

McIntyre and colleagues conducted this study at 77 sites across 12 countries from June 202 to February 2022. They enrolled outpatients aged 18 to 65 years with a DSM-5 diagnosis of MDD who were experiencing partial response to SSRI monotherapy for ≥ 6 weeks and who were deemed suitable candidates for switching antidepressants.

Other inclusion criteria included a duration of current depressive episode of ≥ 3 and < 12 months and a baseline Montgomery-Åsberg Depression Rating Scale (MADRS) total score of ≥ 24 points. Exclusion criteria were any other current DSM-5 psychiatric disorder, treatment-resistant depression, a baseline Digit Symbol Substitution Test score ≥ 70, a history of alcohol or substance use within the past 6 months, and clinically significant suicidal ideation.

After discontinuation of SSRI monotherapy, participants were randomized 1:1 to treatment with vortioxetine 10 or 20 mg/day (all patients up-titrated to 20 mg after 1 week) or desvenlafaxine 50 mg/day for 8 weeks, plus a 4-week safety follow-up period. Participants were assessed with the MARDS, the Clinical Global Impression (CGI) severity and improvement scales, and the Functioning Assessment Short Test (FAST).

Health-related quality of life was assessed using the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q). Safety was evaluated by treatment-emergent adverse events (TEAEs) and the Columbia-Suicide Severity Rating Scale. Planned randomization of 600 patients provided 85% statistical power for concluding non-inferiority.

The primary endpoint was changed from baseline to week 8 in MADRS total score and was analyzed using a mixed model for repeated measures. Non-inferiority was defined as the upper bound of the 95% Ci not exceeding 2.5 MADRS points. Secondary endpoints included changes from baseline to week 8 in CGI-S, FAST, and Q-LES-Q scores, and the CGI-I score at week 8, analyzed by mixed models for repeated measures.

Response was defined as a ≥ 50% reduction in MADRS total score or a CGI-I score of ≤ 2 from baseline to week 8. Remission was defined as a MADRS total score of ≤ 10 or CGI-S score of ≤ 2.

Approximately 603 participants were randomized and received at least 1 dose of study medication (310 vortioxetine and 293 desvenlafaxine). The mean participant age was 43 years, 71% of participants were female, and 92% were Caucasian. Escitalopram (42%) and sertraline (36%) were the most frequently used prior SSRIs. The mean baseline MADRS total score was 31 and CGI-I was 4.5.

Participants reported severely impaired patient functioning, poor health-related quality of life at baseline, and low satisfaction with prior SSRI treatment. In the vortioxetine group, 89% of participants received 20 mg/day from week 1 to week 8. Dose reduction was requested for 7% of patients in the desvenlafaxine group; however, doses remained unchanged.

Depressive symptom reduction from baseline to week 8 was comparable (numeric difference of 0.5 MADRS points in favor of vortioxetine). Significantly more vortioxetine-treated patients achieved symptomatic and functional remission (33% vs 25%, OR=1.5). Response rates were similar between the 2 treatments.

Improvements in FAST total score and Q-LES-Q were comparable between the 2 groups, with significantly greater improvements in FAST autonomy (daily functioning) and interpersonal relationships (social functioning) and a Q-LES-Q medication satisfaction score (28% versus 24%) in vortioxetine-treated patients.

TEAEs, mostly mild or moderate, were reported in 46% and 40% of patients in the vortioxetine and desvenlafaxine groups, respectively. The most common TEAEs in both groups were nausea, headache, and dizziness, with nausea being more frequent in the vortioxetine group (20% vs 9%). The majority (≥ 97%) of patients did not experience suicidal ideation or behavior during the study period.

Study Conclusions

The investigators performed the first head-to-head study vortioxetine versus SNRI in patients with MDD and partial response to SSRI monotherapy. Given comparable efficacy, and significantly higher symptomatic and functional remission, results support earlier use of vortioxetine in the treatment of patients with MDD failing to respond to initial SSRI. Vortioxetine-treated patients had greater improvements in daily and social functioning, as well as greater medication satisfaction.

Study strengths included the direct head-to-head comparison between 2 treatments. The primary study limitation was the relatively short trial duration (8 weeks). Another limitation was a potential expectation bias, given the ability for participants in the desvenlafaxine group to request dose adjustment, which was not implemented.

The Bottom Line

There is evidence in this trial for superior clinical benefits of vortioxetine versus SNRI in patients with MDD and partial response to SSRI monotherapy. Findings support earlier use of vortioxetine in associated treatment algorithms.

Dr Miller is a professor in the Department of Psychiatry and Health Behavior at Augusta University in Georgia. He is on the Editorial Board and serves as the schizophrenia section chief for Psychiatric Times®. The author reports that he receives research support from Augusta University, the National Institute of Mental Health, and the Stanley Medical Research Institute.


1. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D reportAm J Psychiatry. 2006;163(11):1905-1917.

2. Goodwin GM, Price J, De Bodinat C, Laredo J. Emotional blunting with antidepressant treatments: a survey among depressed patientsJ Affect Disord. 2017;221:31-35.

3. Bauer M, Severus E, Möller HJ, Young AH; WFSBP Task Force on Unipolar Depressive Disorders. Pharmacological treatment of unipolar depressive disorders: summary of WFSBP guidelinesInt J Psychiatry Clin Pract. 2017;21(3):166-176.

4. Stahl SM. Modes and nodes explain the mechanism of action of vortioxetine, a multimodal agent (MMA): modifying serotonin's downstream effects on glutamate and GABA (gamma amino butyric acid) releaseCNS Spectr. 2015;20(4):331-336.

5. Wang G, Gislum M, Filippov G, Montgomery S. Comparison of vortioxetine versus venlafaxine XR in adults in Asia with major depressive disorder: a randomized, double-blind studyCurr Med Res Opin. 2015;31(4):785-794.

6. Mahableshwarkar AR, Zajecka J, Jacobson W, et al. A randomized, placebo-controlled, active-reference, double-blind, flexible-dose study of the efficacy of vortioxetine on cognitive function in major depressive disorder [published correction appears in Neuropsychopharmacology. 2016 Nov;41(12 ):2961]. Neuropsychopharmacology. 2015;40(8):2025-2037.

7. McIntyre RS, Florea I, Pedersen MM, Christensen MC. Head-to-head comparison of vortioxetine versus desvenlafaxine in patients with major depressive disorder with partial response to SSRI therapy: results of the VIVRE StudyJ Clin Psychiatry. 2023;84(4):23m14780.

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