Key messages

• We are uncertain whether vortioxetine increases response to treatment or if it reduces anxious symptoms as the certainty of the evidence has been assessed as very low.
• Vortioxetine may increase nausea (low certainty evidence).

What is the evidence.
See evidence matrix in Epistemonikos later

We identified seven systematic reviews [5], [6], [7], [8], [9], [10], [11] including five primary studies reported in seven references [12], [13], [14], [15], [16], [17], [18], all of which were randomised trials. 

One of the trials [18] was excluded because it analysed the long-term effectiveness of vortioxetine for generalised anxiety disorder in adults (i.e., relapse prevention), by including patients who had already been treated with vortioxetine in a previous open-label stage, for 20 weeks prior to randomisation.

What types of patients were included*

All the trials [12], [13], [14], [15] included patients older than 18 years with a diagnosis of generalised anxiety disorder, based on the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Text Revision (DSM-IV-TR) criteria, without a current treatment. It should be noted that one of the trials [13] delimited the inclusion age up to 65 years.

Each randomised trial [12], [13], [14], [15] included patients with greater than or equal score to 20 on the Hamilton Anxiety Rating Scale (HAM-A), and greater than or equal score to 2 in the first two items of the scale (i.e., anxious mood and tension). Similarly, patients with a total score of less than or equal to 16 on the Montgomery – Åsberg Depression Rating Scale were recruited in all the trials [12], [13], [14], [15].

All the trials [12], [13], [14], [15] excluded patients with other psychiatric comorbidities and/or other severe medical illnesses; patients with a recent history of substance abuse or suicidal ideation; and patients who have had a failed response to any previous treatment based on selective serotonin reuptake inhibitors or serotonin and norepinephrine reuptake inhibitors, correctly used (i.e., time and adequate doses) for the current anxiety episode.

What types of interventions were included*

In all the trials [12], [13], [14], [15] the use of oral vortioxetine once daily was compared with placebo. 

Three trials [13], [14], [15] evaluated the use of vortioxetine 5 mg per day and two trials [12], [13], [16], vortioxetine 2.5 mg per day and 10 mg per day.

What types of outcomes 
were measured

• Response to treatment (defined as greater than or equal reduction to 50% of the total score on Hamilton Anxiety Rating Scale initially measured).
• Remission (defined as a total score less than or equal to 7 obtained in the Hamilton Anxiety Rating Scale at the end of the follow-up).
• Anxious symptoms: change of the total score obtained initially in the Hamilton Anxiety Rating Scale, at the end of the follow-up.
• Adverse effects (nausea*).

To whom this evidence does and does not apply

• To whom this evidence does and does not applyThe findings of this summary apply to adult patients with generalised anxiety disorder who have not received prior treatments for the current anxiety episode.
• Our results do not apply to patients with psychiatric comorbidities (e.g., psychotic disorders, bipolar affective disorder, among others) or severe medical conditions (e.g., severe neurological disorders, among others).
• Our results do not apply to patients with suicide risk (i.e., suicidal ideation or attempt) or with a history of substance abuse.

• According to the authors' judgment, this summary includes critical outcomes for health decision-making (such as response to treatment or changes in anxious symptoms), which is reaffirmed by reports [19] , [20] included in the Core Outcome Measures in Effectiveness Trials initiative (COMET) platform. However, according to the same studies [19], [20], new explorations that consider clinically relevant adverse effects (such as sexual dysfunction or increased body mass), and the social and/or occupational functioning, are needed.

• An adequate balance risk/benefit due is not possible due to the existing uncertainty of evidence regarding the decrease of anxious symptoms and the increase of the adverse effects (nausea) associated with vortioxetine. In fact, the evidence related to adverse effects associated with vortioxetine is controversial.
• Among the adverse effects most frequently reported by the randomised trials included in this summary, were: nausea, dry mouth, diarrhea, constipation, anorexia, headache, dizziness, drowsiness, vomiting, among others.

• None of the included studies conducted a cost-effectiveness analysis. However, vortioxetine compared to first-line antidepressants used for generalised anxiety disorder in adults, is a high-cost drug, so its use would imply considerable resource expense. However, implementation of this alternative lacks support as long as the certainty of the evidence regarding to its effectiveness and acceptability remains unavailable.

• As stated in a qualitative study [21], a prioritary point for patients who use antidepressants is finding a drug with minimal adverse consequences. Regarding first-line drugs for generalised anxiety disorder in adults, patients express much concern about sexual dysfunction and weight gain [21]. In this sense, emerging novel therapeutic options that promise another profile of adverse effects, such as vortioxetine, generate expectation. 
• According to the authors' opinion, therapists consider that greater certainty of the evidence is required to contemplate vortioxetine within the pharmacological arsenal for generalised anxiety disorder in adults. In turn, it should be noted that patients should be informed of the lack of evidence regarding the effectiveness and profile of adverse effects of vortioxetine, and its high cost compared to other recommended drugs with greater certainty of the evidence (such as the first line of treatment).

Differences between this summary and other sources

• We detected some discrepancies among the findings of the systematic reviews identified in our comprehensive search [5], [6], [7], [8], [9], [10], [11], despite these included the same primary studies. This could be explained by the existence of methodological errors, presumably in data extraction. This is why new correctly developed systematic reviews are required, in addition to new randomised trials comparing vortioxetine with the first line of treatment.
• The canadian clinical practice guidelines [3] suggest the vortioxetine as an alternative second-line psychopharmacological treatment for generalised anxiety disorder in adults. While in the german guidelines [22] and in the National Institute for Health and Care Excellence recommendations [23] its use is not recommended.

• It is highly likely that the information provided by this summary will change with future trials, due to the very low levels of certainty that the body of evidence currently has.
• We found no systematic reviews or randomised trials ongoing in PROSPERO or ClinicalTrials.gov registers, respectively.