Review
Meta-analysis of randomized controlled trials to assess the effectiveness and safety of free and easy Wanderer plus, a polyherbal preparation for depressive disorders

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Abstract

Free and Easy Wanderer Plus (FEWP) is a polyherbal preparation which therapeutic benefits have been extensively evaluated in patients with various depressive disorders. The purpose of this meta-analysis was to assess the overall effectiveness and safety of FEWP. Following systematic review, a total of 14 high-quality randomized controlled trials (RCTs) were identified and included in the meta-analysis. Statistically greater treatment effects were found in FEWP monotherapy compared to placebo and in FEWP combined with conventional anti-depressants (CADs) compared to CADs alone. Patients taking FEWP alone and combined with CADs experienced fewer adverse events of dizziness, headache, dry mouth, nausea, and constipation compared to CADs alone. These data suggest that FEWP may be an effective herbal agent in treating depressive symptoms. The addition of FEWP also enhances antidepressant effects of CADs. FEWP may have a higher safety profile compared to CADs.

Introduction

Depression is a common psychiatric disorder that is associated with a variety of symptoms affecting mood, cognition, and behavior. Depression is observed in all age groups, and displays an incidence of at least 15% (World Health Organization, 2002). Despite the fact that tricyclic anti-depressants (TCAs), selective serotonin re-uptake inhibitors (SSRIs), and monoamine oxidase inhibitors (MOIs) are widely used to treat depressive symptoms, the response to these anti-depressants are not clinically meaningful for many patients who suffer from depression. In addition, patients often discontinue treatment with anti-depressants due to their adverse events (Furukawa et al., 2003; Moncrieff et al., 2004). In China, Free and Easy Wanderer Plus (FEWP) (also called Jiawei-Xiaoyao-San in Chinese or Kami shoyo san in Japanese) has been prescribed to treat depression on its own or in conjunction with conventional anti-depressants (CADs), such as fluoxetine and carbamazepine.

FEWP, a well-known ancient polyherbal preparation, has long been used in Asia, Europe, and North America for the alleviation of a variety of symptoms, including mood swings, irritability, premenstrual tension, and menopausal syndromes (Maciocia, 1994, Yamada and Kanba, 2007, Zhang, 2004). The preparation was developed from Xiaoyao San, a classic herbal formula that has been used in China for approximately one thousand years (Qin et al., 2009a, Zhang et al., 2008), and FEWP is currently included in the Chinese Pharmacopoeia (2010 edition).

FEWP contains the following herbs: Chaihu (Radix Bupleuri), Danggui (Radix Angelicae sinensis), Baishao (Radix Paeoniae alba), Baishu (Rhizoma Atractylodis macrocephalae), Fuling (Poria Cocos), Shengjiang (Rhizoma Zingiberis recens), Gancao (Radix Glycyrrhizae) and Bohe (Herba Menthae). Besides the herbs mentioned above, FEWP contains many other herbs on occasion based on the theory of traditional Chinese medicine, such as Danpi (Cortex Moutan), Zhizi (Fructus Gardeniae), Houpu (Cortex Magnoliae Officinalis), Zhiqiao (Fructus Aurantii), Gegen (Radix Puerariae), and Dazao (Fructus Jujubae) (Qin et al., 2009b). Additionally, geniposide, paeoniflorin, liquiritin, hesperidin, naringin, paeonol, daidzein, glycyrrhizic acid, honokiol, and magnolol have been identified within the preparation, and these components may be used as markers for quality control (Xie et al., 2007, Zhang et al., 2008).

Recent studies demonstrate that FEWP may elicit biological effects consistent with antidepressant properties. These effects may be associated with the regulation of the following neurotransmitters and neuromodulators, including central GABAA/benzodiapine, 5-hydroxytryptamine (5-HT), and dopamine receptors as well as neurosteroid and cytokine activity (Ushiroyama et al., 2004, Bao et al., 2008, Oh et al., 2007, Wang and Qin, 2010). Furthermore, several individual herbs in FEWP display antidepressant activity. For example, Chaihu has been shown to increase the neurotransmitter content of both norepinephrine and dopamine in the rat brain (Zhang and Gao, 2006), and studies indicate that Baishao, Danggui and Shengjiang exert neuroprotective effects in a model of depression (Shao et al., 2008, Zhang et al., 2007c, Wang et al., 2008). Likewise, Shengjiang has also been shown to mediate the interaction of 5-HT1A/1B and 5-HT2C receptors (Wang et al., 2008). In addition, several studies suggest that zingerone, triterpenoids, gardenoside, saikosaponin and paeonol exert neuroprotective effects (Kabuto et al., 2005, Ge et al., 2008, Bai et al., 2008). Shishkina et al. (2006) found that the interaction of fluoxetine with glycyrrhizic acid activates dopamine metabolism in the striatum, an essential neurobiological pathway for the regulation of behavioral response. Notably, the administration of FEWP has also yielded a potential effect associated with multi-target therapy.

However, high-quality evidence that clearly demonstrates the antidepressant efficacy of FEWP has not yet been systematically studied. Therefore, the primary objective for this study was to determine the effects of FEWP in the treatment of depression disorder utilizing a meta-analysis approach. The meta-analysis was conducted in monotherapy as well as in combination with conventional antidepressant agents.

Section snippets

Inclusion and exclusion criteria

The following criteria were utilized to determine eligible for inclusion in the meta-analysis: (i) the study was a randomized controlled trial (RCT) and limited to only human subjects; (ii) methodological quality of the study was assessed using five-point Jadad scale (Jadad et al., 1996), and only studies rated three points or higher were included; (iii) the diagnoses of depressive disorders were based on standardized diagnostic criteria that defined the severity of depressive symptoms, such as

Eligible studies

The electronic search strategy identified 159 potentially relevant published studies after accurate evaluation of the abstracts by the authors. In cases of disagreement as to whether an article was relevant, the full original article was retrieved for assessment. Of the 159 resulting studies, sixteen studies were excluded because they were animal experimental studies (Fig. 1). Additionally, most of the RCTs were rated as poor-quality RCTs (Jadad score ≤ 2). Ultimately, fourteen RCTs were

Adverse events

Nine RCTs reported information on adverse events (Chen, 2003, Li et al., 2005, Li et al., 2008 and Li et al., 2009, Luo et al., 2006, He and Ren, 2008, Zhang et al., 2007a, Ma, 2007, Xie et al., 2009). In these nine trials, the most common adverse events were nausea, blurred vision, constipation, dry mouth, fatigue, tachycardia, insomnia, somnolence, dizziness and headache. The adverse events of FEWP were constipation, dry mouth, tachycardia, dizziness and headache (Chen, 2003, Li et al., 2008,

Discussion

In total, fourteen RCTs were identified and included in the meta-analysis according to the inclusion criteria. While the evidence remains weak, the results of the present meta-analysis confirm that the benefit profile for FEWP is favorable. Interestingly, the benefits of CADs seem to be significantly enhanced when CADs are combined with FEWP. Furthermore, some evidence suggests that FEWP display fewer adverse events, as compared to CADs.

Named after the drugs’ molecular structure, TCAs were

Conclusion

Our data suggested that FEWP represents a valid anti-depressive agent. However, we did not provide adequate evidence to conclude whether FEWP was superior, inferior or the same as CADs in terms of efficacy for the treatment of depressive symptoms. However, the efficacy of CADs was significantly enhanced when CADs were combined with FEWP. Therefore, some evidence indicates that FEWP may be safer than CADs in the treatment of depressive disorders. Given the small number of discrepant studies

Role of funding source

No any fund agencies listed herein have roles in the design, conduct and data analysis of this work.

Author contribution

We declare that there is no contributors.

Conflict of interest

All authors declare that they have no any conflict of interest in this study.

Acknowledgments

This project was supported by the National Natural Science Foundation of China (No. 30872570).

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