Chin J Integr Med
•1•
EVIDENCE-BASED INTEGRATIVE MEDICINE Wendan Decoction (温胆汤) for Treatment of Schizophrenia: A Systematic Review of Randomized Controlled Trials CHE Yi-wen (车轶文), YAO Ke-yu (姚克宇), XI Yu-peng (席玉棚), CHEN Zi-jie (陈子杰), LI Yong-le (李永乐), YU Ning (于 宁), and ZHAI Shuang-qing (翟双庆) Objective:: To assess the beneficial and adverse effects of Wendan Decoction (温胆汤, WDD) for ABSTRACT Objective Methods:: Five electronic databases were searched until May 2014, including the the treatment of schizophrenia. Methods Chinese National Knowledge Infrastructure, the Chinese Biomedical Literature Database, the Chinese Scientist Journal Database, PubMed, and the Cochrane Central Register of Controlled Trials in the Cochrane Library. The randomized controlled trials (RCTs) testing WDD against placebo, antipsychotic drugs, or WDD combined with antipsychotic drugs against antipsychotic drugs alone were included. Study selection, data extraction, Results:: Thirteen quality assessment, and data analyses were conducted according to the Cochrane standards. Results RCTs (involving 1,174 patients) were included and the methodological quality was evaluated as generally low. The pooled results showed that WDD combined with antipsychotic drugs were more effective in clinical comprehensive effect, Positive and Negative Syndrome Scale (PANSS) scores and Brief Psychiatric Rating Scale scores compared with antipsychotic drugs alone. However, WDD had less effectiveness compared with antipsychotics in clinical comprehensive effect; and WDD was not different from antipsychotic drugs for PANSS scores. The side effects were significantly reduced in the intervention group compared with the control group. Conclusions:: WDD appears to be effective on improving symptoms in patients with schizophrenia. However, due Conclusions to poor methodological quality in the majority of the included trials, the potential benefit from WDD needs to be confirmed in rigorous trials and the design and reporting of trials should follow the international standards. KEYWORDS Wendan Decoction, schizophrenia, randomized controlled trial, systematic review
than 40 species antipsychotic drugs have been used clinically, including phenothiazines, thioxanthone class, butyrophenones, benzamides and two phenoxy nitrogen level classes. (6) The common side effects include somnolence, fatigue, insomnia, nausea, nervousness, dry mouth, weight gain and blurred vision.
Schizophrenia is a common and severe mental illness with a chronic course. (1) It is characterized by basic personality change, division of thinking, emotion and behavior, inharmonious of mentation and the environment.(2) A comprehensive global survey concluded that schizophrenia affects approximately 1% of the population worldwide, (3) which usually presents in early adulthood or late adolescence,(4) and patients dramatically lose their labor capacity. All of these bring significant burden for both families and society. According to the World Health Organization (WHO) in 2001, the total direct costs of schizophrenia are estimated to be about 2.8% of the total healthcare budget.(5)
Wendan Decoction (温胆汤, WDD) comes from an ancient book of Chinese medicine (CM), Valuable Prescriptions for Emergency (Qian Jin Fang) in 652 AD. In this book, it was said that WDD was usually used to treat some mental symptoms such as auditory hallucination, sleep disorders, and irritable. WDD
Schizophrenia is commonly treated with antipsychotic drugs. In addition, other kinds of psychological interventions, such as cognitive behavior therapies, interpersonal therapy, psychotherapy and counseling, were also used. Antipsychotics therapy effect is primarily to block the D2 receptors, affects the brain cortex midbrain dopamine-pathway and the midbrain-limbic system. Nine categories, more
©The Chinese Journal of Integrated Traditional and Western Medicine Press and Springer-Verlag Berlin Heidelberg 2015 Supported by the Specialized Research Fund for the Doctoral Program of Higher Education (No. 20120013110002) School of Basic Medical Sciences, Beijing University of Chinese Medicine, Beijing (100029), China Correspondence to: Prof. ZHAI Shuang-qing, Tel: 8613501362098, E-mail: [email protected] DOI: 10.1007/s11655-015-2047-z
Chin J Integr Med
•2•
was composed of Rhizoma Pinelliae , Pericarpium Citri Reticulatae , Poria , Radix Glycyrrhizae , Rhizoma Coptidis , Fructus Aurantii Immaturus , and Caulis Bombusae in Taeniam , which could invigorate the Spleen (Pi), harmonize the Stomach (Wei), regulate qi, and dispel phlegm. Biochemically, WDD may increase the ability of learning and memory through improving the content and function of central glutamate, and preventing or delaying the degeneration of hippocampal neuronal cells.(7) Studies have shown that Chinese herbal medicine has been used to treat millions of people with schizophrenia for thousands of years; it may improve some outcomes in schizophrenia. (8) Now, in many CMs in the treatment of schizophrenia, the use of WDD or integrated with antipsychotic drugs is the most common. To assess the position and function of WDD in treating schizophrenia, this paper conducted system evaluation based on the randomized controlled trials (RCTs) of WDD in treating schizophrenia, in order to obtain the evidence of the effect and safety of WDD in the treatment of schizophrenia, providing evidence of evidence-based medicine for the treatment of CM.
METHODS
disease duration of the participants were not limited in the trails. The control intervention has to be either WM or placebo. There was no limitation for treatment durations. Herbal decoction used in the original trials should be labeled by the trial authors to be "WDD" or "modified WDD". Duplicated publications of the same groups of participants were excluded. Outcome measures included the clinical comprehensive effect (CCE), Positive and Negative Syndrome Scale (PANSS) scores, Brief Psychiatric Rating Scale (BPRS) scores, and clinical global impression (CGI) scores. The criteria "cure, significant effective, effective, or ineffective" was also included in the outcome measurement.
Data Extraction and Quality Assessment Che YW and Yao KY had extracted some valuable data from some specific research independently. The extracted data included authors, year of publication, total number of cases, diagnosis standard, intervening measure, control measures, treatment course, follow-up, outcome indicator for each study. Disagreements between the investigators were resolved by discussion and reached agreements through a third party.
Database and Search Strategies Five databases were selected for all the clinical trials about WDD or WDD combined with antipsychotic drugs for the treatment of schizophrenia, including the Chinese National Knowledge Infrastructure (CNKI), the Chinese Biomedical Literature Database (CBM), the Chinese Scientist Journal Database (VIP), PubMed, and the Cochrane Central Register of Controlled Trials in the Cochrane Library (until May 2014). The reference lists of retrieved papers were also searched. The search terms were used alone or combined. The most frequent ones were as follows: "schizophrenia," "Wendan Powder," "Wendan San", "Wendan Pills", "Chinese medicine", "combined with," "controlled clinical trial," "clinical trial," and "randomized controlled trials."
Cochrane Handbook for Systematic Review of Interventions, Version 5.1.0 was used by Xi YP and Chen ZJ independently as the trial criteria of methodological quality.(9) The items contained 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. The quality was classified to 3 types of bias including "low", "unclear" and "high". Accordingly, there were 3 levels: low risk of bias (all the items were in low risk of bias), high risk of bias (at least one item was in high risk of bias), and unclear risk of bias (at least one item was in unclear).
Inclusion and Exclusion Criteria
Data Analysis
Inclusion criteria included all published studies or RCTs comparing modified WDD with at least one control group that used the conventional Western medicine (WM) or placebo. Participants should be diagnosed as schizophrenia by investigators. Population characteristics, gender, age, language, or
The statistical package (RevMan5.2.0) provided by Cochrane Collaboration was used for data analyses. Dichotomous data were expressed as risk ratio (RR), with their 95% confidence intervals (CIs), respectively. Meta-analysis was performed if the intervention, control and outcome were the same or
Chin J Integr Med
•3•
similar. The statistical heterogeneity was examined with the I 2 -test, where I 2 values of 50% or more were considered to be an indicator of a substantial heterogeneity.(10) But due to the high heterogeneity in CM, the random effects model was considered to use. To maximize the similarities among studies that would be combined, data were further stratified where possible into subgroups based on different types of interventions.
RESULTS Description of Included Trials Five databases were searched, and finally 242 potentially relevant references were identified through the electronic and manual searches. After reading the titles and abstracts, 213 articles of them were excluded because of duplicated publication (108 studies), animal studied (36 studies), and noncontrolled clinical trials (69 studies). Full texts of 29 papers were retrieved, and finally 13 RCTs(11-23) were included (Figure 1). All the RCTs were conducted in China and published in Chinese.
Records screened (n =134)
Records excluded (n =105) Sixteen articles were excluded with reasons listed as follows: - Participants did not meet the inclusive criteria (n =1); - Duplication (n =2); - No control group (n =5); - Intervention included other Chinese herbal formula (n =4); - No data for extraction (n =3); - Unfound articles (n =1).
Eligibility
Records after duplicates removed (n =134)
Full-text articles assessed for eligibility (n =29)
Included
Identification
Additional records identified through other sources (n =0)
Screening
Records identified through database searching (n =242)
Studies included in the review (n =13)
Figure 1.
Flowchart of Trials Selection Process
The characteristics of the 13 trials are listed in Table 1. Among the 13 trials, 1,174 patients with schizophrenia were included. There was a wide variation in the age of subjects (15–60 years). Thirteen trials specified four diagnostic criteria of schizophrenia: 9 trials(12-14,16-18,20-22)
used Chinese Classification of Mental Disorders (CCMD) Ⅲ, among them, 8 trials(12-14,16-18,21,22) used CCMD Ⅲ alone, 1 trial(20) combined with WM and CM classification and diagnostic criteria on schizophrenia; 1 trial(11) used CCMD Ⅱ combined with WM and CM classification and diagnostic criteria on schizophrenia; 2 trials(19,23) used International Classification of Diseases (ICD) Ⅹ alone; 1 trial(15) used Pathergasiology(24) alone. Of the 13 trials, 10 trials(11,13,15-17,19-23) researched two groups of test, 3 trials(12,14,18) researched three groups of test. Interventions included all the prescriptions based on WDD alone or combined with antipsychotic drugs. The controls included antipsychotic drugs or combined with WDD. Three trials(12,14,18) investigated modified WDD used alone versus antipsychotics drugs, 3 three-arm trials(12,14,18) and the rest 10 trials(11,13,15-17,19-23) compared modified WDD plus antipsychotic drugs versus antipsychotic drugs. The different compositions of WDD are presented in Table 2. The total treatment duration ranged 14–60 days. Eleven(12-14,16-23) of the 13 trials used PANSS as the outcome measure, other two kinds of scales including BPRS and CGI. Side effect was evaluated by Rating Scale for Extrapyramidal Side Effects (RSESE) and Treatment-Emergent Symptom Side Effect (TESS) Scale. Nine trials (11,13,16,17,19-23) used four classes to evaluate treatment effects including cure, significant effective, effective and ineffective, while other 4 trials (12,14,15,18) used three classes (except of cure) according to the scores reducing rate.
Methodological Quality of Included Trials The majority of the 13 trials were assessed to be of general poor according to the predefined quality assessment criteria (Figure 2). The randomized allocation of participants was mentioned in all trials; but only 1 trial (22) stated the methods or sequence generation including random number table and 2 trials(11,16) stated the methods or sequence generation without concrete information. There was insufficient information provided to judge whether or not it was conducted properly. One trial (22) mentioned the allocation concealment, blinding of participants and personnel, and blinding of outcome assessment, but it was not specifically described. No trial reported dropout or withdraw, and none of them had a pretrial estimation of sample size. Only 1 trial(15) mentioned follow-up, and the period remained 12 months. We
Chin J Integr Med
•4•
Table 1. Study
Characteristics and Methodological Quality of Included Studies
Sample Diagnosis standard
Intervention
Control
Course Follow-up Outcome indicator (Day) (Month)
Meng ZR 1998(11)
63
CCMD Ⅱ, WM and CM classification and diagnostic criteria on schizophrenia
Modified WDD plus sulpiride
Sulpiride
30
—
Clinical effect, BPRS, RSESE
Tan B 2006(12)
90
CCMD Ⅲ
Ⅰ Modified WDD Ⅱ Modified WDD plus clozapine
Clozapine
60
—
Clinical effect, PANSS, TESS
Wang RC 2008(13)
60
CCMD Ⅲ
Modified WDD plus chlorpromazine
Chlorpromazine
42
—
Clinical effect, PANSS , TESS
Chang W 2009(14)
90
CCMD Ⅲ
Ⅰ Modified WDD Ⅱ Modified WDD plus chlorpromazine
Chlorpromazine
60
—
Clinical effect, PANSS, TESS
Peng DY 2010(15)
72
Pathergasiology
Modified WDD plus risperidone
Risperidone
60
12
Clinical effect, BPRS, TESS
Shi LR 2010(16)
78
CCMD Ⅲ
Modified WDD plus sulpiride
Haloperidol
14
—
Clinical effect, PANSS, TESS
Ge X 2012(17)
112
CCMD Ⅲ
Modified WDD plus chlorpromazine
Chlorpromazine
56
—
Clinical effect, PANSS, CGI, TESS
Dou NJ 2012(18)
120
CCMD Ⅲ
Ⅰ Modified WDD Ⅱ Modified WDD plus risperidone
Risperidone
60
—
Clinical effect, PANSS,TESS
Guo YJ 2013(19)
50
ICD Ⅹ
Modified WDD plus quetiapine fumarate
Quetiapine fumarate
42
—
Clinical effect, PANSS, TESS
Li L 2013(20)
107
CCMD Ⅲ, WM and CM classification and diagnostic criteria on schizophrenia
Modified WDD plus risperidone
Risperidone
56
—
Clinical effect, PANSS, TESS
Sun ZT 2014(21)
54
CCMD Ⅲ
Modified WDD plus aripiprazole
Aripiprazole
60
—
Clinical effect, PANSS, RSESE
Shao H 2014(22)
200
CCMD Ⅲ
Modified WDD plus quetiapine fumarate and olanzapine; or modified WDD plus perphenazine, risperidone and clozapine
Quetiapine fumarate and olanzapine or perphenazine, risperidone and clozapine
42
—
Clinical effect, PANSS, BPRS, TESS
ICD Ⅹ
Modified WDD plus olanzapine
Olanzapine
56
—
Clinical effect, PANSS, TESS
Zhang GM 2014(23)
78
tried to contact the author for more information; however, no information was got.
plus antipsychotic drugs with antipsychotic drugs.
CCE Random sequence generation (selection bias) Allocation concealment (selction bias) Blinding of participants and personnel (performance bias) Blinding of outcome assessment (detection bias) Incomplete outcome data (attrition bias) Selective reporting (reporting bias) Other bias 0% Low risk of bias
Figure 2.
Unclear risk of bias
25%
50%
75%
100%
High risk of bias
Risk of Bias of Included Studies
Effect of Interventions WDD plus Antipsychotic Drugs versus Antipsychotic Drugs Thirteen trials(11-23) compared the modified WDD
All trials used CCE to evaluate the outcome. Seven trials (13,16,17,19-21,23) used the percentage of PANSS scores reduced rate to measure the outcome: cure (PANSS scores reduced rate 75%), significant effective (PANSS scores reduced rate 50%–74%), effective (PANSS scores reduced rate 25%–49%) and ineffective (PANSS scores reduced rate
•1•
EVIDENCE-BASED INTEGRATIVE MEDICINE Wendan Decoction (温胆汤) for Treatment of Schizophrenia: A Systematic Review of Randomized Controlled Trials CHE Yi-wen (车轶文), YAO Ke-yu (姚克宇), XI Yu-peng (席玉棚), CHEN Zi-jie (陈子杰), LI Yong-le (李永乐), YU Ning (于 宁), and ZHAI Shuang-qing (翟双庆) Objective:: To assess the beneficial and adverse effects of Wendan Decoction (温胆汤, WDD) for ABSTRACT Objective Methods:: Five electronic databases were searched until May 2014, including the the treatment of schizophrenia. Methods Chinese National Knowledge Infrastructure, the Chinese Biomedical Literature Database, the Chinese Scientist Journal Database, PubMed, and the Cochrane Central Register of Controlled Trials in the Cochrane Library. The randomized controlled trials (RCTs) testing WDD against placebo, antipsychotic drugs, or WDD combined with antipsychotic drugs against antipsychotic drugs alone were included. Study selection, data extraction, Results:: Thirteen quality assessment, and data analyses were conducted according to the Cochrane standards. Results RCTs (involving 1,174 patients) were included and the methodological quality was evaluated as generally low. The pooled results showed that WDD combined with antipsychotic drugs were more effective in clinical comprehensive effect, Positive and Negative Syndrome Scale (PANSS) scores and Brief Psychiatric Rating Scale scores compared with antipsychotic drugs alone. However, WDD had less effectiveness compared with antipsychotics in clinical comprehensive effect; and WDD was not different from antipsychotic drugs for PANSS scores. The side effects were significantly reduced in the intervention group compared with the control group. Conclusions:: WDD appears to be effective on improving symptoms in patients with schizophrenia. However, due Conclusions to poor methodological quality in the majority of the included trials, the potential benefit from WDD needs to be confirmed in rigorous trials and the design and reporting of trials should follow the international standards. KEYWORDS Wendan Decoction, schizophrenia, randomized controlled trial, systematic review
than 40 species antipsychotic drugs have been used clinically, including phenothiazines, thioxanthone class, butyrophenones, benzamides and two phenoxy nitrogen level classes. (6) The common side effects include somnolence, fatigue, insomnia, nausea, nervousness, dry mouth, weight gain and blurred vision.
Schizophrenia is a common and severe mental illness with a chronic course. (1) It is characterized by basic personality change, division of thinking, emotion and behavior, inharmonious of mentation and the environment.(2) A comprehensive global survey concluded that schizophrenia affects approximately 1% of the population worldwide, (3) which usually presents in early adulthood or late adolescence,(4) and patients dramatically lose their labor capacity. All of these bring significant burden for both families and society. According to the World Health Organization (WHO) in 2001, the total direct costs of schizophrenia are estimated to be about 2.8% of the total healthcare budget.(5)
Wendan Decoction (温胆汤, WDD) comes from an ancient book of Chinese medicine (CM), Valuable Prescriptions for Emergency (Qian Jin Fang) in 652 AD. In this book, it was said that WDD was usually used to treat some mental symptoms such as auditory hallucination, sleep disorders, and irritable. WDD
Schizophrenia is commonly treated with antipsychotic drugs. In addition, other kinds of psychological interventions, such as cognitive behavior therapies, interpersonal therapy, psychotherapy and counseling, were also used. Antipsychotics therapy effect is primarily to block the D2 receptors, affects the brain cortex midbrain dopamine-pathway and the midbrain-limbic system. Nine categories, more
©The Chinese Journal of Integrated Traditional and Western Medicine Press and Springer-Verlag Berlin Heidelberg 2015 Supported by the Specialized Research Fund for the Doctoral Program of Higher Education (No. 20120013110002) School of Basic Medical Sciences, Beijing University of Chinese Medicine, Beijing (100029), China Correspondence to: Prof. ZHAI Shuang-qing, Tel: 8613501362098, E-mail: [email protected] DOI: 10.1007/s11655-015-2047-z
Chin J Integr Med
•2•
was composed of Rhizoma Pinelliae , Pericarpium Citri Reticulatae , Poria , Radix Glycyrrhizae , Rhizoma Coptidis , Fructus Aurantii Immaturus , and Caulis Bombusae in Taeniam , which could invigorate the Spleen (Pi), harmonize the Stomach (Wei), regulate qi, and dispel phlegm. Biochemically, WDD may increase the ability of learning and memory through improving the content and function of central glutamate, and preventing or delaying the degeneration of hippocampal neuronal cells.(7) Studies have shown that Chinese herbal medicine has been used to treat millions of people with schizophrenia for thousands of years; it may improve some outcomes in schizophrenia. (8) Now, in many CMs in the treatment of schizophrenia, the use of WDD or integrated with antipsychotic drugs is the most common. To assess the position and function of WDD in treating schizophrenia, this paper conducted system evaluation based on the randomized controlled trials (RCTs) of WDD in treating schizophrenia, in order to obtain the evidence of the effect and safety of WDD in the treatment of schizophrenia, providing evidence of evidence-based medicine for the treatment of CM.
METHODS
disease duration of the participants were not limited in the trails. The control intervention has to be either WM or placebo. There was no limitation for treatment durations. Herbal decoction used in the original trials should be labeled by the trial authors to be "WDD" or "modified WDD". Duplicated publications of the same groups of participants were excluded. Outcome measures included the clinical comprehensive effect (CCE), Positive and Negative Syndrome Scale (PANSS) scores, Brief Psychiatric Rating Scale (BPRS) scores, and clinical global impression (CGI) scores. The criteria "cure, significant effective, effective, or ineffective" was also included in the outcome measurement.
Data Extraction and Quality Assessment Che YW and Yao KY had extracted some valuable data from some specific research independently. The extracted data included authors, year of publication, total number of cases, diagnosis standard, intervening measure, control measures, treatment course, follow-up, outcome indicator for each study. Disagreements between the investigators were resolved by discussion and reached agreements through a third party.
Database and Search Strategies Five databases were selected for all the clinical trials about WDD or WDD combined with antipsychotic drugs for the treatment of schizophrenia, including the Chinese National Knowledge Infrastructure (CNKI), the Chinese Biomedical Literature Database (CBM), the Chinese Scientist Journal Database (VIP), PubMed, and the Cochrane Central Register of Controlled Trials in the Cochrane Library (until May 2014). The reference lists of retrieved papers were also searched. The search terms were used alone or combined. The most frequent ones were as follows: "schizophrenia," "Wendan Powder," "Wendan San", "Wendan Pills", "Chinese medicine", "combined with," "controlled clinical trial," "clinical trial," and "randomized controlled trials."
Cochrane Handbook for Systematic Review of Interventions, Version 5.1.0 was used by Xi YP and Chen ZJ independently as the trial criteria of methodological quality.(9) The items contained 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. The quality was classified to 3 types of bias including "low", "unclear" and "high". Accordingly, there were 3 levels: low risk of bias (all the items were in low risk of bias), high risk of bias (at least one item was in high risk of bias), and unclear risk of bias (at least one item was in unclear).
Inclusion and Exclusion Criteria
Data Analysis
Inclusion criteria included all published studies or RCTs comparing modified WDD with at least one control group that used the conventional Western medicine (WM) or placebo. Participants should be diagnosed as schizophrenia by investigators. Population characteristics, gender, age, language, or
The statistical package (RevMan5.2.0) provided by Cochrane Collaboration was used for data analyses. Dichotomous data were expressed as risk ratio (RR), with their 95% confidence intervals (CIs), respectively. Meta-analysis was performed if the intervention, control and outcome were the same or
Chin J Integr Med
•3•
similar. The statistical heterogeneity was examined with the I 2 -test, where I 2 values of 50% or more were considered to be an indicator of a substantial heterogeneity.(10) But due to the high heterogeneity in CM, the random effects model was considered to use. To maximize the similarities among studies that would be combined, data were further stratified where possible into subgroups based on different types of interventions.
RESULTS Description of Included Trials Five databases were searched, and finally 242 potentially relevant references were identified through the electronic and manual searches. After reading the titles and abstracts, 213 articles of them were excluded because of duplicated publication (108 studies), animal studied (36 studies), and noncontrolled clinical trials (69 studies). Full texts of 29 papers were retrieved, and finally 13 RCTs(11-23) were included (Figure 1). All the RCTs were conducted in China and published in Chinese.
Records screened (n =134)
Records excluded (n =105) Sixteen articles were excluded with reasons listed as follows: - Participants did not meet the inclusive criteria (n =1); - Duplication (n =2); - No control group (n =5); - Intervention included other Chinese herbal formula (n =4); - No data for extraction (n =3); - Unfound articles (n =1).
Eligibility
Records after duplicates removed (n =134)
Full-text articles assessed for eligibility (n =29)
Included
Identification
Additional records identified through other sources (n =0)
Screening
Records identified through database searching (n =242)
Studies included in the review (n =13)
Figure 1.
Flowchart of Trials Selection Process
The characteristics of the 13 trials are listed in Table 1. Among the 13 trials, 1,174 patients with schizophrenia were included. There was a wide variation in the age of subjects (15–60 years). Thirteen trials specified four diagnostic criteria of schizophrenia: 9 trials(12-14,16-18,20-22)
used Chinese Classification of Mental Disorders (CCMD) Ⅲ, among them, 8 trials(12-14,16-18,21,22) used CCMD Ⅲ alone, 1 trial(20) combined with WM and CM classification and diagnostic criteria on schizophrenia; 1 trial(11) used CCMD Ⅱ combined with WM and CM classification and diagnostic criteria on schizophrenia; 2 trials(19,23) used International Classification of Diseases (ICD) Ⅹ alone; 1 trial(15) used Pathergasiology(24) alone. Of the 13 trials, 10 trials(11,13,15-17,19-23) researched two groups of test, 3 trials(12,14,18) researched three groups of test. Interventions included all the prescriptions based on WDD alone or combined with antipsychotic drugs. The controls included antipsychotic drugs or combined with WDD. Three trials(12,14,18) investigated modified WDD used alone versus antipsychotics drugs, 3 three-arm trials(12,14,18) and the rest 10 trials(11,13,15-17,19-23) compared modified WDD plus antipsychotic drugs versus antipsychotic drugs. The different compositions of WDD are presented in Table 2. The total treatment duration ranged 14–60 days. Eleven(12-14,16-23) of the 13 trials used PANSS as the outcome measure, other two kinds of scales including BPRS and CGI. Side effect was evaluated by Rating Scale for Extrapyramidal Side Effects (RSESE) and Treatment-Emergent Symptom Side Effect (TESS) Scale. Nine trials (11,13,16,17,19-23) used four classes to evaluate treatment effects including cure, significant effective, effective and ineffective, while other 4 trials (12,14,15,18) used three classes (except of cure) according to the scores reducing rate.
Methodological Quality of Included Trials The majority of the 13 trials were assessed to be of general poor according to the predefined quality assessment criteria (Figure 2). The randomized allocation of participants was mentioned in all trials; but only 1 trial (22) stated the methods or sequence generation including random number table and 2 trials(11,16) stated the methods or sequence generation without concrete information. There was insufficient information provided to judge whether or not it was conducted properly. One trial (22) mentioned the allocation concealment, blinding of participants and personnel, and blinding of outcome assessment, but it was not specifically described. No trial reported dropout or withdraw, and none of them had a pretrial estimation of sample size. Only 1 trial(15) mentioned follow-up, and the period remained 12 months. We
Chin J Integr Med
•4•
Table 1. Study
Characteristics and Methodological Quality of Included Studies
Sample Diagnosis standard
Intervention
Control
Course Follow-up Outcome indicator (Day) (Month)
Meng ZR 1998(11)
63
CCMD Ⅱ, WM and CM classification and diagnostic criteria on schizophrenia
Modified WDD plus sulpiride
Sulpiride
30
—
Clinical effect, BPRS, RSESE
Tan B 2006(12)
90
CCMD Ⅲ
Ⅰ Modified WDD Ⅱ Modified WDD plus clozapine
Clozapine
60
—
Clinical effect, PANSS, TESS
Wang RC 2008(13)
60
CCMD Ⅲ
Modified WDD plus chlorpromazine
Chlorpromazine
42
—
Clinical effect, PANSS , TESS
Chang W 2009(14)
90
CCMD Ⅲ
Ⅰ Modified WDD Ⅱ Modified WDD plus chlorpromazine
Chlorpromazine
60
—
Clinical effect, PANSS, TESS
Peng DY 2010(15)
72
Pathergasiology
Modified WDD plus risperidone
Risperidone
60
12
Clinical effect, BPRS, TESS
Shi LR 2010(16)
78
CCMD Ⅲ
Modified WDD plus sulpiride
Haloperidol
14
—
Clinical effect, PANSS, TESS
Ge X 2012(17)
112
CCMD Ⅲ
Modified WDD plus chlorpromazine
Chlorpromazine
56
—
Clinical effect, PANSS, CGI, TESS
Dou NJ 2012(18)
120
CCMD Ⅲ
Ⅰ Modified WDD Ⅱ Modified WDD plus risperidone
Risperidone
60
—
Clinical effect, PANSS,TESS
Guo YJ 2013(19)
50
ICD Ⅹ
Modified WDD plus quetiapine fumarate
Quetiapine fumarate
42
—
Clinical effect, PANSS, TESS
Li L 2013(20)
107
CCMD Ⅲ, WM and CM classification and diagnostic criteria on schizophrenia
Modified WDD plus risperidone
Risperidone
56
—
Clinical effect, PANSS, TESS
Sun ZT 2014(21)
54
CCMD Ⅲ
Modified WDD plus aripiprazole
Aripiprazole
60
—
Clinical effect, PANSS, RSESE
Shao H 2014(22)
200
CCMD Ⅲ
Modified WDD plus quetiapine fumarate and olanzapine; or modified WDD plus perphenazine, risperidone and clozapine
Quetiapine fumarate and olanzapine or perphenazine, risperidone and clozapine
42
—
Clinical effect, PANSS, BPRS, TESS
ICD Ⅹ
Modified WDD plus olanzapine
Olanzapine
56
—
Clinical effect, PANSS, TESS
Zhang GM 2014(23)
78
tried to contact the author for more information; however, no information was got.
plus antipsychotic drugs with antipsychotic drugs.
CCE Random sequence generation (selection bias) Allocation concealment (selction bias) Blinding of participants and personnel (performance bias) Blinding of outcome assessment (detection bias) Incomplete outcome data (attrition bias) Selective reporting (reporting bias) Other bias 0% Low risk of bias
Figure 2.
Unclear risk of bias
25%
50%
75%
100%
High risk of bias
Risk of Bias of Included Studies
Effect of Interventions WDD plus Antipsychotic Drugs versus Antipsychotic Drugs Thirteen trials(11-23) compared the modified WDD
All trials used CCE to evaluate the outcome. Seven trials (13,16,17,19-21,23) used the percentage of PANSS scores reduced rate to measure the outcome: cure (PANSS scores reduced rate 75%), significant effective (PANSS scores reduced rate 50%–74%), effective (PANSS scores reduced rate 25%–49%) and ineffective (PANSS scores reduced rate
