Wei ZHENG, Ying-Qiang XIANG, Gabor S. UNGVARI, Helen F.K. CHIU, Chee H. NG,Ying WANG, Yu-Tao XIANG*

?Systematic review and meta-analysis?

Huperzine A for treatment of cognitive impairment in major depressive disorder: a systematic review of randomized controlled trials

Wei ZHENG1, Ying-Qiang XIANG2,3, Gabor S. UNGVARI4,5, Helen F.K. CHIU6, Chee H. NG7,Ying WANG8, Yu-Tao XIANG9,*

depression; meta-analysis; cognitive function; huperzine A; adjunctive treatment

1. Introduction

Major depressive disorder (MDD) is a common psychiatric illness that is often associated with cognitive dysfunction.[1]One hypothesis about the mechanism of cognitive decline in MDD links it to decreasing acetylcholinesterase (AChE) activity of the cholinergic system in the hippocampus, frontal cortex, and septum.[2]Some studies suggest that AChE inhibitors(e.g., donepezil,[3]rivastigmine,[4]and galantamine[5])can ameliorate cognitive impairment in animal models of depression and in humans with MDD.[5-7]Huperzine A (HupA) is a Traditional Chinese Medicine (TCM)isolated from Huperzineserrata (a genus of clubmosses),also known as ground pines or creeping cedar, in the family Lycopeodiaceae (a family of fern-allies). It is a powerful, highly specific, and reversible inhibitor of AChE.[8-10]Because of its popularity as a TCM medication in mainland China, extensive clinical experience and research about HupA in China may help clarify the mechanism of action for its potential efficacy in the treatment of MDD. However, to date no systematic review or meta-analysis on HupA augmentation for MDD has been published. The primary aim of this study was to conduct a systematic review and meta-analysis about the efficacy and safety of HupA in the treatment of MDD based on published RCTs identified by searching international and Chinese databases.

2. Methods

2.1 Types of studies

All publications of randomized controlled trials (RCTs)which reported on the efficacy and/or safety of antidepressants combined with HupA in the treatment of MDD were eligible for inclusion. Case reports/series,observational trials, meta-analyses, and systematic reviews were excluded.

2.2 Outcome measures

The primary outcome measure of interest was cognitive function measured by the Wisconsin Card Sorting Test (WCST)[11]or the Wechsler Memory Scale-Revised, Chinese version (WMS-RC).[12]Key secondary outcomes were improvement in depressive and anxiety symptoms assessed by the Hamilton Depression Rating Scale (HAMD)[13]and the Hamilton Anxiety Rating Scale (HAMA),[14]self-reported quality of life assessed by the General Quality of Life Inventory of the World Health Organization (WHOQOL-100),[15]causes for discontinuation of treatment, and adverse drug reactions measured by the Dosage Record Treatment Emergent Symptom Scale (DOTES).[16]Clinical outcomes were based on intent-to-treat (ITT) analysis.

2.3 Selection of studies

PubMed, PsycINFO, Embase, Cochrane Library databases, the Cochrane Controlled Trials Register,ClinicalTrials.gov (https://www.clinicaltrials.gov/),and Chinese databases (WanFang Database, Chinese Biomedical database, and China Journal Net) were searched from the inception of the databases through March 12, 2016 using the following search terms:(Depressive Disorders OR Disorder, Depressive OR Disorders, Depressive OR Neurosis, Depressive OR Depressive Neuroses OR Depressive Neurosis OR Neuroses, Depressive OR Depression, Endogenous OR Depressions, Endogenous OR Endogenous Depression OR Endogenous Depressions OR Depressive Syndrome OR Depressive Syndromes OR Syndrome, Depressive OR Syndromes, Depressive OR Depression, Neurotic OR Depressions, Neurotic OR Neurotic Depression OR Neurotic Depressions OR Melancholia OR Melancholias OR Unipolar Depression OR Depression, Unipolar OR Depressions, Unipolar OR Unipolar Depressions) AND(Huperzine A OR Huperzine OR HupA) AND (randomized controlled trial OR controlled clinical trial OR randomized OR placebo OR drug therapy OR randomly OR trial OR groups). We also hand-searched reference lists from identified and relevant review articles for additional studies and contacted authors for unpublished data.

2.4 Data extraction

Two authors (ZW and XYQ) independently conducted the literature search and extracted the data. Any disagreement was resolved by a third author (XYT). Data presented only in graphs and figures were extracted whenever possible. Authors were contacted to obtain missing information or clarification if possible. If cases were from multicenter studies, whenever possible, data were extracted separately for each center.

2.5 Statistical methods

We used RevMan (version 5.1.7.0) in this meta-analysis according to the recommendations of the Cochrane Collaboration. For continuous data, weighted mean difference (WMD) with 95% CI was used to compare groups, and for dichotomous data, risk ratio (RR)with 95% confidence intervals (Cis) were computed to compare groups. The I2statistic assessed statistical heterogeneity between the three studies: when I2≥50%,a random effects model was used;[17]otherwise, a fixed effect model was employed.[18]All analyses were twotailed with alpha set at 0.05.

2.6 Risk of bias assessment

The methods of random sequence generation (selection bias), allocation concealment (selection bias), blinding of participants and personnel (performance bias), blinding of outcome assessment (detection bias), incomplete outcome data (attrition bias), selective reporting(reporting bias), and other biases were assessed using the Risk of Bias (ROB) scale developed to assess RCTs by the Cochrane Collaboration.[19]

3. Results

3.1 Results of the literature search

The search yielded 54 potentially relevant articles, of which four articles were published in English and 50 in Chinese. Of the 54 studies, 3 RCTs met the inclusion criteria.[20-22]As shown in Figure 1, the total number of subjects included in the three studies was 238, with 119 receiving an antidepressant augmentated with HupA and 119 only receiving an antidepressant.

3.2 The characteristics of included studies

As shown in Table 1, all three RCTs[20-22]were conducted in China and used the criteria of the Chinese Classification of Mental Disorders, 3rd edition(CCMD-3)[23]to diagnose depression. Males accounted for 45.4% of the sample (range 30% to 58% in the three studies), the weighted mean age of participants was 29.6 (range 16-60) years; and the weighted mean duration of illness was 3.3 (range 1.2 to 5.2) years. The weighted mean duration of the treatment trial reported in the studies was 6.7 (range 6-8) weeks. None of the studies were supported by pharmaceutical companies.

3.3 Assessment of risk of bias

Figure 1. Identification of included studies

Table 1. Characteristics of included studies

Table 2. Evaluation of risk of bias in the three included studies

The risk of different types of biases of the three studies is shown in Table 2. Two studies[21-22]mentioned“random” assignment without a description of the method of randomizing, and one RCT[20]was rated as high risk of selection bias because patients were classified into two groups according to the order of admission. None of the studies were blinded so the risk of allocation bias, performance bias, and detection bias were high. The studies reported the outcomes of all enrolled subjects, so the risk of attrition bias was low; but in the absence of study registration materials it was impossible to determine whether or not there was selective reporting (i.e., reporting bias). There was no evidence of other types of biases (e.g., drug company sponsorship of the study). Overall, all three studies were considered at high risk of bias and, thus, relatively lowquality studies.

Because there were only three RCTs included in the meta-analysis, publication bias could not be tested.[24]

3.4 Changes in severity of depressive symptoms

In all three studies there were differences between groups in changes of the total HAMD score overthe study period. As shown in Figure 2, one of the studies[22]reported a significantly greater reduction of depressive symptoms (based on the HAMD) when adjunctive HupA was provided to patients with MDD being treated with antidepressants, but the other two studies did not find a significant advantage of adjunctive treatment with HupA. When pooling the three studies in a random effects meta-analysis, there was no statistically significant difference in the improvement in depressive symptoms between MDD patients who only received antidepressants and those who received antidepressants and adjunctive HupA.

Figure 2. Adjunctive Huperzine A for MDD: forest plot for improvement in depressive symptoms assessed by change in total score of the Hamilton Depression Scale

3.5 Cognitive results

The other results from the three studies are shown in Table 3. Only two studies[20,21]assessed the cognitive effects of the treatment. Both studies reported a significant advantage of using adjunctive HupA. In one study,[21]memory functioning at the end of the 8-week trial was better in patients taking antidepressants with adjunctive HupA than in those who were only taking antidepressants. In another study,[20]several measures of executive functioning derived from the WCST were significantly better at the end of the 6-week trial in depressed patients taking antidepressants with adjunctive HupA. These cognitive outcome measures were quite different so it was not possible to pool the results of the two studies into a meta-analysis.

3.6 Other results

The level of anxiety was only assessed in one of the studies.[22]Based on the total score of the HAMA at the end of the 6-week trial, there was no significant difference in the severity of anxiety symptoms between the two groups (Table 3).

Only one study[20]assessed quality of life. As measured by WHOQOL-100,[15]quality of life was significantly better at the end of the trial in individuals who received combined treatment with antidepressants and HupA (Table 3).

Only one study[22]assessed adverse reactions. The study assessed adverse events using the DOTES[16]which considers tachycardia, dysuria, electrocardiographic abnormality, dry mouth, drowsiness, nausea,constipation, blurred vision, and insomnia. It found no difference in the prevalence of adverse events between the two treatment groups

None of the included RCTs reported the rate or causes of treatment discontinuation.

4. Discussion

4.1 Main finding

Despite an extensive review of both English-language and Chinese-language literature, we only identified three RCTs that assessed the potential benefit of adjunctive HupA when treating individuals with depression who are currently using antidepressants. All three studies were open label and the outcome evaluation in the trials was not blinded, so the overall strength of the studies was rated as ‘poor’. The pooled sample from the three studies, all of which were published in Chinese,was 238 individuals, but it was only possible to conduct a meta-analysis for the results related to changes in depressive symptoms because other outcomes of interest (e.g., cognitive changes, quality of life changes,etc.) were only considered in one or two of the studies.Overall, the results suggest that adjunctive treatment with HupA over 6 to 8 weeks in patients with depression who are currently taking antidepressants does notresult in a better reduction of depressive symptoms,but it does appear to lead to less cognitive impairment in depressed individuals and, possibly, to a better selfreported quality of life for depressed individuals.

Table 3. Comparison of cognitive function, anxiety, and quality of life in patients with depression at end of course of treatment with either antidepressants and adjunctive HupA (experimental group) or with antidepressants alone (control group)

4.2 Limitations

The small number of studies identified and the limited measures employed in the identified studies made it impossible to conduct a full meta-analysis, so we could not do a sensitivity analysis or subgroup analyses, and we could not construct a funnel plot to assess potential publication bias. Specifically, there were not enough studies with data on cognitive functioning to conduct a meta-analysis of this important outcome. Moreover, the relatively low quality of the available studies (open label,non-blinded) and the relatively short duration of the studies (from 6 to 8 weeks) means that the findings that were significant – the benefit of HupA augmentation for cognitive functioning and quality of life in depressed patients – are not robust; they need to be replicated in larger, methodologically more rigorous RCTs that follow participants for much longer.

4.3 Importance

Despite the limited number of RCTs identified and the methodological limitations of the identified studies,[25]this review does provide some support for the suggestion that AChE inhibitors such as HupA can ameliorate the cognitive decline that is often associated with depression and, possibly, improve the quality of life of individuals being treated for depression with antidepressant medications. Similar to our findings, a recent meta-analyses[26]found that adjunctive HupA is an effective choice for improving cognitive function in individuals with schizophrenia. The mechanism of action of HupA in improving cognitive functioning (or preventing cognitive decline) remains unknown, but given the importance of cognitive impairment in a wide range of mental disorders, further work in this promising area is merited.

Funding

The study was supported by the Start-up Research Grant(SRG2014-00019-FHS) and the Multi-Year Research Grant (MYRG2015-00230-FHS) from the University of Macau. Trial registration number: CRD42015024796(http://www.crd.york.ac.uk/prospero/)

Conflict of interest statement

The authors report no conflict of interest in conducting this study and preparing the manuscript.

Authors’ contribution

WZ designed the study and was assisted by YQX and YTX in the search for papers, data extraction, and analysis.WZ and YTZ drafted the manuscript. GSU, HFKC, CHN,and YW made critical revisions to the manuscript. All authors approved the final version for publication.

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(received, 2016-01-11; accepted, 2016-03-20)

Dr. Wei Zheng obtained a bachelor’s degree from Hebei Medical University in 2012 and a master’s degree of psychiatry from Capital Medical University in Beijing in 2015. He is currently a resident psychiatrist in the Department of Psychiatry at the Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital) in Guangdong Province, China.

石杉?jí)A甲對(duì)重度抑郁癥患者認(rèn)知功能障礙的治療：一項(xiàng)隨機(jī)對(duì)照試驗(yàn)的系統(tǒng)綜述

鄭偉,向應(yīng)強(qiáng), Ungvari GS, Chiu F.K. H, Ng H. C, 王穎, 項(xiàng)玉濤

抑郁癥；meta分析；認(rèn)知功能；石杉?jí)A甲

Background:Acetylcholinesterase (AChE) inhibitors have been shown to be effective in treating cognitive impairment in animal models and in human subjects with major depressive disorder (MDD). Huperzine A(HupA), a Traditional Chinese Medicine derived from a genus of clubmosses known as Huperzineserrata, is a powerful AChE inhibitor that has been used as an adjunctive treatment for MDD, but no meta-analysis on HupA augmentation for MDD has yet been reported.Aim:Conduct a systematic review and meta-analysis of randomized controlled trials (RCTS) about HupA augmentation in the treatment of MDD to evaluate its efficacy and safety.Methods:Two evaluators independently searched nine English-language and Chinese-language databases,selected relevant studies that met pre-determined inclusion criteria, extracted data about outcome and safety, and conducted quality assessments and data synthesis.Results:Three low-quality RCTs (pooled n=238) from China were identified that compared monotherapy antidepressant treatment for depression versus combined treatment with antidepressants and HupA.Participants in the studies ranged from 16 to 60 years of age. The average duration of adjunctive antidepressant and HupA treatment in the studies was only 6.7 weeks. All three studies were open label and non-blinded, so their overall quality was judged as poor. Meta-analysis of the pooled sample found no significant difference in the improvement in depressive symptoms between the two groups (weighted mean difference: -1.90 (95%CI: -4.23, 0.44), p=0.11). However, the adjunctive HupA group did have significantly greater improvement than the antidepressant only group in cognitive functioning (as assessed by the Wisconsin Card Sorting Test and the Wechsler Memory Scale-Revised) and in quality of life. There was no significant difference in the incidence of adverse drug reactions between groups.Conclusions:The data available on the effectiveness and safety of adjunctive treatment using HupA in patients with MDD who are receiving antidepressants is insufficient to arrive at a definitive conclusion about its efficacy and safety. Pooling of the data from three low-quality RCTs from China found no advantage of adjunctive HupA in the treatment of depressive symptoms, but adjunctive treatment with HupA was associated with a faster resolution of the cognitive symptoms that frequently accompany MDD.Trial registration number:CRD42015024796 (http://www.crd.york.ac.uk/prospero/)

[Shanghai Arch Psychiatry. 2016; 28(2): 64-71.

http://dx.doi.org/10.11919/j.issn.1002-0829.216003]

1The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou, China

2China Clinical Research Center for Mental Disorders, Beijing, China, and Center of Depression, Beijing Institute for Brain Disorders, Beijing, China

3Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, China

4School of Psychiatry and Clinical Neurosciences, University of Western Australia, Perth, Australia

5University of Notre Dame Australia / Marian Centre, Perth, Australia

6Department of Psychiatry, Chinese University of Hong Kong, Hong Kong SAR, China

7Department of Psychiatry, University of Melbourne, Melbourne, Victoria, Australia

8Institute of Chinese Medical Sciences, University of Macau, Macao SAR, China

9Unit of Psychiatry, Faculty of Health Sciences, University of Macau, Macao SAR, China

*correspondence: Dr. Yu-Tao Xiang, 3/F, Building E12, Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau SAR,China. E-mail: xyutly@gmail.com

A full-text Chinese translation of this article will be available at http://dx.doi.org/10.11919/j.issn.1002-0829.216003 on August 25, 2016.

背景：乙酰膽堿酯酶 (Acetylcholinesterase, AChE) 抑制劑在重性抑郁障礙 (Major Depressive Disorder, MDD) 的動(dòng)物模型和人類患者中已被證實(shí)可以有效地治療認(rèn)知障礙。石杉?jí)A甲 (Huperzine A, HupA) 是一種來(lái)自于被稱為蛇足石杉 (Huperzineserrata) 的石松屬傳統(tǒng)中醫(yī)藥，是一種強(qiáng)有力的AChE抑制劑，已被用于抑郁癥的輔助治療，但有尚無(wú)關(guān)石杉?jí)A甲對(duì)MDD的強(qiáng)化治療作用的meta分析。目標(biāo)：對(duì)有關(guān)石杉?jí)A甲強(qiáng)化治療抑郁癥的隨機(jī)對(duì)照試驗(yàn)進(jìn)行系統(tǒng)綜述和meta分析，評(píng)估其療效及安全性。方法：兩位評(píng)估者獨(dú)立檢索9個(gè)英文和中文數(shù)據(jù)庫(kù)，選擇符合預(yù)先確定的納入標(biāo)準(zhǔn)的相關(guān)研究，提取有關(guān)療效和安全性的數(shù)據(jù)，并進(jìn)行質(zhì)量評(píng)估和數(shù)據(jù)擬合合成。結(jié)果：納入了三項(xiàng)中國(guó)低質(zhì)量的隨機(jī)對(duì)照試驗(yàn)（總共n=238），這些試驗(yàn)比較了單用抗抑郁藥治療抑郁癥與抗抑郁藥和石杉?jí)A甲的聯(lián)合治療，試驗(yàn)中的被試從16歲到60歲。研究中石杉?jí)A甲輔助抗抑郁藥治療的平均時(shí)間僅為6.7周。這三項(xiàng)研究都是公開標(biāo)簽未使用盲法，所以他們的總體質(zhì)量評(píng)定為差。總體樣本的Meta分析發(fā)現(xiàn)兩組抑郁癥狀的改善沒(méi)有顯著性差異（差異加權(quán)差為-1.90，95%CI可信區(qū)間為-4.23至0.44，p=0.11）。然而，石杉?jí)A甲輔助治療組比單用抗抑郁藥治療組在認(rèn)知功能和生活質(zhì)量方面有顯著改善（如威斯康星卡片分類測(cè)驗(yàn)、韋氏記憶量表修訂的評(píng)估）。組間藥物不良反應(yīng)的發(fā)生率無(wú)顯著性差異。結(jié)論：有關(guān)在接受抗抑郁藥的MDD患者使用HupA輔助治療的療效和安全性的可獲取數(shù)據(jù)不足，難以得出有關(guān)其療效和安全性的明確結(jié)論。匯集國(guó)內(nèi)3項(xiàng)低質(zhì)量的RCT數(shù)據(jù)沒(méi)有發(fā)現(xiàn)采用輔助使用HupA治療抑郁癥狀的優(yōu)勢(shì)，但輔助使用HupA與更快改善經(jīng)常伴隨MDD出現(xiàn)的認(rèn)知癥狀相關(guān)。試驗(yàn)注冊(cè)號(hào)碼：CRD42015024796 (http://www.crd.york.ac.uk/prospero/)

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