What is the role of vortioxetine in treating anxiety, specifically generalized anxiety disorder (GAD) or social anxiety disorder?

Vortioxetine for Anxiety Disorders

Vortioxetine should not be used for treating generalized anxiety disorder (GAD) or social anxiety disorder, as current evidence does not support its efficacy for these conditions. 1, 2, 3

Guideline Position on Vortioxetine

The Japanese Society of Anxiety and Related Disorders/Japanese Society of Neuropsychopharmacology explicitly excludes vortioxetine from their 2023 social anxiety disorder guideline recommendations. 1 While one RCT demonstrated efficacy and acceptability for social anxiety disorder, meta-analysis was unavailable and insufficient to warrant inclusion in treatment recommendations. 1

The guideline clearly states that vortioxetine was "not included in the guideline, with or without recommendations" because it has not been adequately studied. 1

Evidence Against Vortioxetine for GAD

Primary Research Findings

Multiple randomized controlled trials and meta-analyses demonstrate that vortioxetine fails to separate from placebo for GAD treatment: 2, 3

• A 2016 meta-analysis of 1,843 patients found no significant improvement in GAD symptoms at any dose (2.5 mg, 5 mg, or 10 mg daily) compared to placebo. 2
• The 2.5 mg dose showed OR=1.16 (95% CI=0.84-1.60, p=0.38), 5 mg showed OR=1.41 (95% CI=0.82-2.41, p=0.21), and 10 mg showed OR=1.05 (95% CI=0.76-1.46, p=0.75). 2
• A pivotal 2014 RCT (n=457) failed to achieve statistical significance on the primary endpoint (HAM-A total score reduction) for both 2.5 mg and 10 mg doses versus placebo. 3

Contradictory Evidence Requiring Caution

Some meta-analyses suggest potential benefit in severe GAD only: 4, 5

• A 2015 meta-analysis found vortioxetine superior to placebo overall (SMD=-0.118, p=0.007), with greater benefit in severe GAD (baseline HAM-A ≥25; SMD=-0.338, p=0.002). 4
• A 2018 meta-analysis showed pooled effect size of -2.95 (95% CI=-4.37 to -1.53, p<0.01) for HAM-A change from baseline. 5
• However, remission rates were not significantly different from placebo (pooled OR=1.06,95% CI=0.86-1.30, p=0.62). 5

Critical limitation: These positive meta-analyses were based on limited RCTs with inconsistent results, and the authors themselves urged caution in clinical translation. 4

Safety Profile

Vortioxetine carries dose-dependent adverse effects without proven efficacy: 2, 3

• Nausea is significantly more frequent at 5 mg (OR=2.99,95% CI=1.31-6.84, p=0.009) and 10 mg doses (OR=2.80,95% CI=1.85-4.25, p<0.00001). 2
• Discontinuation due to adverse events is marginally higher than placebo (OR=1.560,95% CI=1.006-2.419, p=0.047). 4
• Common adverse events include nausea, dry mouth, headache, diarrhea, constipation, and vomiting. 3

Recommended First-Line Alternatives

SSRIs and SNRIs remain the evidence-based pharmacotherapy for anxiety disorders: 1, 6

• SSRIs demonstrate high efficacy (NNT=4.70) with safety profiles comparable to placebo for social anxiety disorder. 1
• Escitalopram and sertraline are preferred initial SSRI choices due to superior efficacy, tolerability, and fewer drug interactions. 6
• SNRIs show comparable efficacy (NNT=4.94) and can be considered when SSRIs fail or are not tolerated. 1
• Duloxetine is FDA-approved for GAD in children ≥7 years and has robust evidence in adults. 6

Exception: MDD with Comorbid GAD

Vortioxetine may have a role when treating major depressive disorder (MDD) with comorbid GAD, not GAD as a primary diagnosis: 7

• An open-label study (n=100) showed 61% MADRS response and 55% HAM-A response at 8 weeks with vortioxetine 10-20 mg/day in patients with severe MDD and severe comorbid GAD. 7
• 52% achieved response on both depression and anxiety scales; 31% achieved remission on both. 7
• This represents treatment of depression with secondary anxiety improvement, not primary anxiety disorder treatment. 7

Clinical Bottom Line

Use established first-line agents (SSRIs/SNRIs) for GAD and social anxiety disorder. 1, 6 Reserve vortioxetine exclusively for its FDA-approved indication of major depressive disorder, where comorbid anxiety symptoms may secondarily improve. 7 The current evidence base does not support using vortioxetine as primary treatment for anxiety disorders. 2, 3