Vortioxetine, a multimodal antidepressant for generalized anxiety disorder: A systematic review and meta-analysis

Highlights

• Vortioxetine modulates 5-HT transporter and different 5-HT receptors leading to control of anxiety.

• Vortioxetine proved a superior short-term efficacy over placebo in reduction of anxiety.

• In a relapse prevention study, vortioxetine was found to be efficacious and tolerable.

• Vortioxetine showed more robust effect in patients with severe anxiety.

• More clinical trial data will be mandatory to support current findings.

Abstract

Vortioxetine has a beneficial pharmacological profile for reducing anxiety and depression. Recently, a number of randomized, double-blind, placebo-controlled clinical trials (RCTs) of vortioxetine have been conducted in patients with generalized anxiety disorder (GAD); however, the results from GAD RCTs are inconsistent. With an extensive search of databases and clinical trial registries, four published short-term RCTs were identified and included in the present meta-analysis. The mean change in total scores on the Hamilton Anxiety Rating Scale (HAMA) from baseline was the primary endpoint. The secondary endpoints included the response and remission rates, as defined by a ≥50% reduction in HAMA total scores and a ≤7 change in the HAMA total score at the end of treatment. In addition, the mean change in the HAMA total score from baseline in the subgroup with a HAMA total score ≥25 at baseline was included. Vortioxetine was significantly more effective than was placebo, with a standardized mean difference (SMD) of −0.118 (95% CIs, −0.203 to −0.033, P = 0.007). In particular, those with severe GAD (HAMA total score ≥25 at baseline) had a significantly greater benefit from vortioxetine than those without (SMD = −0.338, 95% CIs = −0.552 to −0.124, p = 0.002). The odds ratios (ORs) for vortioxetine for response and remission were 1.221 (95% CIs, 1.027 to 1.452, P = 0.024) and 1.052 (95% CIs, 0.853 to 1.296, P = 0.637), respectively. Discontinuation due to adverse events (AEs) (OR = 1.560, 1.006 to 2.419, p = 0.047) was marginally higher in vortioxetine than placebo treatment, whereas discontinuation due to any reason (OR = 0.971, 0.794 to 1.187, p = 0.771) and inefficacy (OR = 0.687, 0.380 to 1.243, p = 0.215) were not significantly different among treatment groups. Although our results suggest that vortioxetine may have a potential as an another treatment option for GAD (especially for severe GAD), they should be interpreted and translated into clinical practice with caution, as the meta-analysis was based on a limited number of RCTs.

Introduction

Generalized anxiety disorder (GAD) is a common psychiatric illness resulting in deteriorating effects on the patient's functional capacity. In fact, GAD patients may have greater impairment in psychosocial functioning than those with major medical illnesses, including type II diabetes, hypertension, recent myocardial infarction, and congestive heart failure (Weisberg et al., 2010). The impairment in patients with GAD is also comparable to that of major depressive disorder (MDD) (Wittchen et al., 2000). GAD has extensive comorbidity with other psychiatric disorders such as MDD, bipolar disorder, and substance disorders as well (Alegria et al., 2010, Kessler et al., 2012). Furthermore, it may increase the odds of suicidal ideation and attempt two-fold; the unadjusted odds ratio ranged from 3 to 8 in National Comorbidity Survey Replication (NCS-R) and National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) samples (Thibodeau et al., 2013). Somatic anxiety symptoms, including restlessness, irritability, muscle tension, sleep disturbances, and fatigue, are commonly found in patients with GAD. In addition, impaired cognitive functions are problematic in these patients (i.e., difficult concentration and decrease of attention). GAD patients commonly present constant worry that the patient or a relative will shortly become ill or have an accident. Indeed, GAD is one of the most common psychiatric conditions leading to a visit to primary care practitioners and GAD patients have a tendency to seek more help from health professionals. Given the aforementioned findings, proper and effective treatment of GAD is indispensable (Combs and Markman, 2014).

According to the recent treatment guidelines (NIHCE, 2004, Baldwin et al., 2014, Bandelow et al., 2012, Katzman et al., 2014), the first-line pharmacotherapy for GAD includes selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), although there is also good evidence for the efficacy of pregabalin and quetiapine. Buspirone, benzodiazepine, and hydroxyzine may also be useful treatment options (Baldwin et al., 2011). Despite numerous pharmacological agents, response rates to initial treatment with an SSRI or SNRI are still inadequate in the treatment of GAD. According to the results from randomized placebo-controlled trials (RCTs), the difference in the response rate measured by global measures (i.e., Clinical Global Impression [CGI] scale) between antidepressants and placebo ranged from 15 to 20% (Baldwin, 2011). In addition, a substantial portion of GAD patients may suffer adverse events (AEs), relapse or recurrence, a discontinuation of symptoms and functional impairments (Baldwin and Nutt, 2012, Baldwin et al., 2011). However, the targets of approved psychotropics for treating GAD are mainly antidepressants that are based on neurotransmitter reuptake inhibition, which is partly attributable to the current limited efficacy of pharmacological treatment in the treatment of GAD (Massart et al., 2012). Therefore, there is a considerable unmet need to develop different pharmacological agents with novel mechanisms of action leading to enhanced effectiveness and greater acceptability when compared with existing agents (Baldwin and Nutt, 2012).

Vortioxetine is a multimodal antidepressant approved for the treatment of major depressive disorder (MDD) with proven efficacy and safety in September 2013 by the US FDA. It exerts reuptake inhibition on the serotonin transporter, increasing the level of 5-HT in the neuronal synapse as well as selectively binding to a variety of other serotonin receptors. It selectively binds to and acts as an antagonist of 5-HT3, 5-HT1D, and 5-HT7 receptors; as a partial agonist to 5-HT1B receptors; and as an agonist of 5-HT1A receptors (Bang-Andersen et al., 2011, Dubovsky, 2014, Guilloux et al., 2013, Stenkrona et al., 2013). The net effects of this pharmacological profile may include the modulation of 5-HT, noradrenaline, dopamine, acetylcholine and histamine in crucial brain regions such as nucleus accumbens, dorsal raphe nucleus, ventral hippocampus and medial prefrontal cortex; such effects could be of either the action or the mechanism, but not both (Sanchez et al., 2015).

Currently, 12 RCTs have been available for the treatment of MDD as published or unpublished (Pae et al., in press). The antianxiety effect of vortioxetine has been consistently observed in subgroup analysis in such MDD trials. For instance, the improvement of anxiety symptoms measured by changes in the Hamilton Rating Scale for Anxiety (HAMA) total score (Hamilton, 1959) was significantly different from baseline in the total score from week 2 or week 3 onward compared to placebo treatment (magnitude of difference from placebo: −3.3 with vortioxetine 5 mg, −3.0 with vortioxetine 10 mg, and −2.9 with venlafaxine) in the first MDD RCT (Alvarez et al., 2012). Such a trend toward a favorable efficacy of vortioxetine in the reduction of anxiety was also replicated in subsequent MDD RCTs (Baldwin et al., 2012a, Boulenger et al., 2014, Katona et al., 2012). In this regard, a number of RCTs of GAD have been recently conducted; however, the efficacy of vortioxetine has been inconsistent across the studies.

Systematic reviews and meta-analyses, especially of newly marketed drugs, are important, as they can overcome the limitations of small sample sizes, increase the generalizability of results by including many trials conducted in various populations, increase the statistical power for group comparisons, investigate potential publication biases, and quantify and analyze inconsistencies in results across clinical studies (Cohn and Becker, 2003, Finckh and Tramer, 2008, Han et al., 2014). Therefore, the present work performed a systematic review and meta-analysis of short-term and long-term RCTs of vortioxetine in patients with GAD to summarize currently available RCTs.