ReviewVortioxetine, a multimodal antidepressant for generalized anxiety disorder: A systematic review and meta-analysis
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.
Section snippets
Data search
PubMed, EMBASE, PsycINFO, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Web of Science, Cochrane Central Register of Controlled Trials Cochrane Library, and ClinicalTrials.gov (www.clinicaltrials.gov) were searched as of 01 August 2014. The search term was “vortioxetine (Lu AA21004).” A final re-search for studies was conducted in the same search engines on 30 October 2014. Reference lists from identified articles and reviews were also used to find additional studies.
Description of studies included in the meta-analysis
Of the 359 records identified by the search of the databases, 292 were excluded, as they were irrelevant to our meta-analysis. The remaining 67 studies were retrieved for more detailed evaluation as seen in Fig. 1.
Four short-term RCTs (Bidzan et al., 2012, Mahableshwarkar et al., 2014a, Mahableshwarkar et al., 2014b, Rothschild et al., 2012) met the inclusion criteria, and one long-term trial was a relapse prevention study (Baldwin et al., 2012b). Of the 38 records obtained from //ClinicalTrials.gov
Discussion
The present meta-analysis demonstrated the statistically superior efficacy of vortioxetine compared with placebo for the treatment of GAD, but it had small differences in terms of mean changes in HAMA total scores from baseline (SMD = −0.118) and in response rates (OR = 1.221); in fact, the remission rate was not different between the two treatment groups. Intriguingly, the mean change in HAMA total scores from baseline was significantly different between the two treatment groups favoring
Conclusion
The definite clinical efficacy of vortioxetine for the short-term control of GAD symptoms remains to be further elucidated with subsequent clinical trials to confirm the practical utility of vortioxetine for treating GAD at this point, although vortioxetine seems to be a well-tolerated agent for GAD treatment and may have a clear efficacy for treating severe GAD based on the currently available findings. However, our results should be interpreted and translated into clinical practice with
Role of funding source
This work was supported by a grant from the Ministry of Health and Welfare (HI12C0003); however, the funding source had no further role in preparation, data collection, and writing of the paper.
Contributors
All authors designed the study. C. Pae, S.-M. Wang, C. Han and S.-J. Lee acquired and analyzed the data, which P. Masand and A. Serretti also analyzed. C. Pae, S.-M. Wang, C. Han, S.-J. Lee and A. Patkar wrote the article, which all authors reviewed and approved for publication.
Competing interest
All authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Acknowledgment
This study was supported by a grant of the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (HI12C0003).
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