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ORIGINAL ARTICLE
Year : 2023 | Volume
: 9
| Issue : 2 | Page : 212-223
Efficacy and duration of electro-acupuncture combined with conventional antipsychotics for schizophrenia: A meta-analysis
Zhao-Han Huang1, Yuan Fang2, Qi Yu1, Tong Wang1
1 aColleg of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
2 Shanghai Center for Women and Children's Health, Shanghai, China
Correspondence Address:
Dr. Tong Wang
Beijing University of Chinese Medicine, Beijing
China
Source of Support: None, Conflict of Interest: None
DOI: 10.4103/2311-8571.372173
Introduction: This study aimed to evaluate the effectiveness and optimal course time of electro-acupuncture (EA) combined with conventional antipsychotics in the treatment of schizophrenia (SZ) and to provide a basis for its clinical application. Methods: Relevant databases and authoritative websites were retrieved, and references were screened up to May 2021. Literature quality evaluation and data extraction were carried out according to the requirements of Cochrane version 5.1.0, and meta-analysis was conducted using Rav Man5.4 software. Results: In total, 16 randomized controlled trails comprising 1352 patients were selected. Meta-analysis revealed that the observation group showed greater improvements than the control group in total clinical efficacy (P < 0.00001, odds ratio [OR] = 3.51, 95% confidence interval [CI] = [2.51, 4.91]), as well as better effective rate of symptom relief (P = 0.02, MD = 3.08, 95% CI = [1.23, 7.71]), and an improved negative symptom score (P = 0.005, MD = −4.50, 95% CI = [−6.52, −2.48]), positive symptom score (P < 0.0001, MD = −1.41, 95% CI = [−2.25, −0.57]), total score (P = 0.001, MD = 9.25, 95% CI = [13.03, 5.47]), and general psychopathological score (P < 0.0001, MD = −2.30, 95% CI = [−4.18, −0.43]) in the Positive and Negative Syndrome Scale (PANSS). However, there was no statistically significant difference between the two groups in the effective rate of adverse reactions (P > 0.05). In the 4–6 weeks following treatment, a significant improvement in all the four components of the PANSS scores was observed in the observation group. Conclusion: The efficacy of EA combined with conventional antipsychotics for SZ is better than that of psychiatric drugs alone. In addition, the effect of a 4-to 6-week treatment course on each outcome index is more significant, and the efficacy is higher.
Keywords: Electro-acupuncture, meta-analysis, schizophrenia
Schizophrenia (SZ) is a debilitating disease, ranked among the top 20 causes of disability worldwide. Despite its commonality, the underlying etiology remains unknown, although it is known to involve obstacles in thinking, emotion, perception, and behavior.[1] SZ affects approximately 1% of the world's population, of whom approximately 10% eventually commit suicide. The protracted and slow progression of this disease places an enormous burden on families and society, and its treatment remains a great challenge.[2] SZ is characterized by a number of pathogenetic factors, including abnormalities related to neurotransmitters, genes, epigenetics, the immune system, and neurodevelopment.[3] Since the development of modern medicine, the main treatment of SZ is symptomatic treatment with conventional western medicine (WM). The most commonly prescribed WMs for SZ are atypical antipsychotic drugs, but there is insufficient evidence to state that existing antipsychotics can substantially improve the long-term outcome of patients with SZ.[4] In addition, antipsychotics can induce to some severe adverse effects, and the cost of treatment is high. For example, olanzapine can increase body weight and serum triglycerides and cholesterol; it can also elicit insulin resistance and reduce glucose effectiveness. Similar to olanzapine, the main adverse effect of clozapine is agranulocytosis, whose cumulative incidence at 1 year of treatment was observed at 0.8%.[5]
Thus, complementary and alternative therapies which avoid the limitations of WM must be sought as a means of treating SZ to. Electro-acupuncture (EA), a combination of acupuncture with electrical stimulation which uses different waveform pulses to generate electrical stimulations to the human body, has been widely used in the treatment of SZ in China. EA adjusts the local or systemic physiological and pathological processes through the meridian to achieve a therapeutic effect.[6] Relevant clinical studies have shown that EA has significant effects on the treatment of mental diseases and can improve the adverse reactions caused by antipsychotics.[7] However, few studies have investigated SZ treatment with EA, the clinical efficacy of different treatment courses of SZ has not yet been systematically reported, and there are also some controversies regarding the optimal treatment timing and course of EA. Hence, it is necessary to integrate and synthesize the evaluation of EA combined with conventional antipsychotics in the treatment of SZ, so as to provide more reliable data support for clinical application.
MethodsLiterature-search strategy
Two investigators retrieved the relevant randomized controlled trails (RCTs) from the following databases: PubMed, Web of science, Embase, The Cochrane Library, SinoMed, China Academic Journals Full-text Database (CNKI), Weipu Database, Wanfang Database, and China Biomedical Database (CBM), from inception until October 2020, with no language or publication status restriction. A comprehensive search strategy was conducted, various combinations of MeSH items and free words were searched synchronously, including “SZ,” “Schizophrenic Disorders,” “EA,” “dianzhen,” etc., (Detailed search strategies can be found). After the search was completed, the literature was imported into note express for management and screening.
Inclusion and exclusion criteria
Inclusion criteria for articles included:
Research design: RCTResearch object: Patients diagnosed with SZ according to clear diagnostic criteria, including under the codes CCMD-3 or DSM-IV or International Classification of Diseases-10Intervention: The control group was treated with pure conventional antipsychotics, and the experimental group was treated with EA and antipsychoticsOutcome indicators: Major outcome: Clinical total effective rate, Positive and Negative Syndrome Scale (PANSS) scale total score, PANSS score scale general psychopathological score, PANSS score scale positive score (Scale for Assessment of Positive Symptoms [SAPS]), PANSS score scale negative score Scale for Assessment of Negative Symptom (SANS). Secondary outcome: Brief Psychiatric Rating Scale (BPRS) score, effective rate of adverse reactions, significant rate of symptom relief.The exclusion criteria included:
Duplicate publicationsNonclinical research (including animal experiments, cell gene research, drug research, meta-analysis, system review, and abstract)The control group included other intervention measures (such as diet intervention and fitness intervention), or the experimental group interventions other than EAUnknown type or dose of medicationThe included patients had other mental illnesses besides SZNo or unclear diagnostic criteriaNo outcome indicators available.Literature data extraction
Preliminary screening of the study was independently conducted by two reviewers. After searching, the duplicated studies were removal from the retrieved studies using noteexpress. Excluded studies were recorded with explanations. During this procedure, disagreements were resolved by discussion or consensus. The main contents of the extracted data were: (1) Basic information of the research object; (2) Research sample size; (3) random sampling, allocation hiding method, blinding realization process, and number of patients lost to follow-up and withdrawals; (4) intervention measures and period of treatment; and (5) outcome indicators.
Literature quality evaluation
The literature quality evaluation was performed following the principles of the Cochrane Handbook for Systematic Reviews of Interventions and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement. It was evaluated from six aspects, including random sequence generation, allocation concealment, blind method, incomplete data, selective reporting of research results and other bias sources, and the bias risk assessment chart was generated.
Statistical analysis
Review Manager 5.4 software was used for the data analysis. The heterogeneity between the results of each included study was tested using the Q test. The random effect model was used for analysis, if there was significant statistical homogeneity among the results (P ≤ 0.1, I2 >50%), the fixed-effect model was used for analysis instead (P > 0.1, I2 ≤50%). For dichotomous variables (counting data), odds ratio (OR) was used as the analysis statistics for efficacy, while for continuous variables (measurement data), mean difference (MD) was used instead. Furthermore, 95% confidence interval (CI) was set for each effect.
Ethics statement
All statistical analyses and data sources were based on previously published studies, therefore, no ethical approval or patient consent was required.
ResultsLiterature selection
The initial search yielded 281 potentially eligible studies. We deleted 34 duplicates and 4 irrelevant studies by checking the title and abstract. After reading the full texts of the remaining records, 14 studies were excluded. Finally, 16 studies[6, 8-22] were included for the statistical analysis [Figure 1]. Study selection was performed in accordance with the PRISMA flowchart.
Figure 1: Flowchart of the literature selection. PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-AnalysesCharacteristics of included trials
In the 16 RCT studies finally selected for analysis, a total of 1352 participants were recruited; the maximum sample size was 200 cases,[10] and the minimum sample size was 60 cases,[12],[13],[14],[15],[18] The mean age ranged from 22 to 52.6, and the duration of illness was mainly 2–24 years. The characteristics of the included studies are summarized in [Table 1].
Assessment of study quality based on risk of bias
All studies mentioned the randomization of participants; however, only four studies clearly indicated that the random number table method was used to generate random sequences. The methods of blinding of participants and outcome assessments were described in only three and two studies, respectively, both of which were assessed as low risk. None of the studies mentioned whether there was an allocation of concealment, and the studies did not have access to relevant protocols to determine whether there was publication bias or other biases, so these aspects were assessed as unclear risks [Figure 2].
Sensitivity analysis
To assess the robustness of our analysis, we performed a sensitivity analysis. The results showed that the response rate, the overall results did not change by excluding any 1 study, indicating that the credibility of the study was high and the conclusion was stable.
Assessment of reporting biases
Reporting biases and small-study effects will be detected by Egger's test and funnel plot [Figure 3] of 8 studies that reported clinical efficacy meta-analysis in clinical efficacy. For Egger's test, a P > 0.10 was considered to indicate no reporting biases or small study effects.
Outcomes
Major outcome
Clinical efficacy
Eight of the 10 included studies provided evidence on the effectiveness of EA and psychiatric drugs therapies for improving total clinical efficacy in SZ patients (I2 = 0%, Z = 7.36, P < 0.00001) [Figure 4].
Total Positive and Negative Syndrome Scale scale score
Seven studies including 487 patients reported the total PANSS scale score. The specific analysis results from the different treatment periods showed slightly different point of view. The effect of EA combined with conventional antipsychotics for SZ was found to be better than that of psychiatric drugs alone in improving the total score of the PANSS scale with treatment cycles of 4-weeks (MD = −6.66, 95% CI: −11.15, −2.17, P = 0.004), 6-weeks (MD = −10.36, 95% CI: −15.97, −4.74, P = 0.03) and 8-weeks (MD = −13.63, 95% CI: −28.89, −2.62, P < 0.00001). Meanwhile, the results of the 2-week treatment course analysis showed that the difference in total PANSS scores between the two groups was not statistically significant [Figure 5] and [Figure 6].
Figure 5: Total PANSS Score of the two groups at 2 weeks of treatment. PANSS: Positive and Negative Syndrome Scale, CI = Confidence interval, SD: Standard deviation
Figure 6: Total PANSS Score of the two groups at 4, 6, and 8 weeks of treatment. PANSS: Positive and Negative Syndrome Scale, CI = Confidence interval, SD: Standard deviationGeneral psychopathological Positive and Negative Syndrome Scale score
Four RCTs compared the general psychopathological scores of the PANSS scale, between the experimental and control groups after the intervention [Figure 7]. Based on the analysis of different treatment cycles, the efficacy of EA combined with conventional psychiatric drugs in the treatment of SZ for 4 and 8 weeks was found to be better than that of drugs alone in improving the general psychopathological score of the PANSS scale. Nevertheless, there was no statistical difference in PANSS psychopathological negative score reduction when comparing the two groups at 2 weeks [Figure 8].
Figure 7: PANSS general psychopathology score of two groups. PANSS: Positive and Negative Syndrome Scale, CI = Confidence interval, SD: Standard deviation
Figure 8: PANSS general psychopathology Score of the two groups at 4、6、8 weeks of treatment. PANSS: Positive and Negative Syndrome Scale, CI = Confidence interval, SD: Standard deviationScale for Assessment of Positive Symptoms score
Seven studies reported SAPS positive scores in a total of 535 patients. Meta-analysis showed that, compared with common antipsychotics, the EA combined with psychiatric drug therapies significantly reduced SAPS positive scores (MD = −1.41, 95% CI: −2.25, −0.57, P = 0.001) [Figure 9]. More specifically, the difference in SAPS positive score between the observation group and the control group at 1, 2, and 4 weeks of treatment was statistically significant, while there was no statistical difference at 8 weeks (MD = −1.57, 95% CI: −3.94, −0.80, P = 0.20), as shown in [Figure 10] and [Figure 11].
Figure 9: SAPS Score of the two groups. SAPS = Scale for Assessment of Positive Symptoms, CI = Confidence interval, SD: Standard deviation
Figure 10: SAPS Score of the two groups at 1 and 2 weeks of treatment. SAPS = Scale for Assessment of Positive Symptoms, CI = Confidence interval, SD: Standard deviation
Figure 11: SAPS Score of the two groups at 4 and 8 weeks of treatment. SAPS = Scale for Assessment of Positive Symptoms, CI = Confidence interval, SD: Standard deviationScale for Assessment of Negative Symptom score
Meta-analysis of 6 RCTs reporting a total of 409 patients with SANS negative score showed that the combined use of EA and psychiatrics therapies was superior to only drugs in reducing SANS negative score in patients with SZ (MD = −4.50, 95% CI: −6.52, −2.48, P = 0.005). Specifically, the course analysis showed that the difference in SANS negative score between the experimental and control groups at 4, 6 and 8 weeks of treatment was statistically significant, while there was no statistical difference at 2 weeks (MD = −1.16, 95% CI: −4.50, −2.18, P = 0.50) [Figure 12] and [Figure 13].
Figure 12: SANS Score of the two groups at 2, 4 and 6 weeks of treatment. SANS: Scale for Assessment of Negative Symptom, CI = Confidence interval, SD: Standard deviation
Figure 13: SANS Score of the two groups at 8 weeks of treatment. SANS: Scale for Assessment of Negative Symptom, CI = Confidence interval, SD: Standard deviationSecondary outcome
Effective symptom relief
Two of the 13 articles included in this study described the obvious effect of symptom relief. Meta-analysis showed that the effective symptom relief of the EA plus conventional antipsychotics group was similar (MD = 4.88, 95%CI: 0.59, 40.39, P > 0.05) with that in the psychiatric drugs alone group after 4 days of treatment [Figure 14]. However, on the 7th day of treatment, patients in the experimental group showed significant higher symptom relief efficiency (MD = 3.08, 95% CI: 1.23, 7.71, P = 0.02) [Figure 15].
Figure 14: Symptom relief of the 2 days of treatment, CI = Confidence interval, SD: Standard deviation
Figure 15: Symptom relief of the 7 days of treatment, CI = Confidence interval, SD: Standard deviationBrief Psychiatric Rating Scale score and the effective rate of adverse reactions
In addition, the results of the studies included respectively from the perspective of BPRS score (MD = −7.00, 95% CI: −20.08, 6.09, P = 0.29) [Figure 16] and the effective rate of adverse reactions (MD = −0.46, 95% CI: 0.14, 1.46, P = 0.19) [Figure 17]) both failed to find any difference among two groups.
Figure 16: BPRS of the two groups. BPRS: Brief Psychiatric Rating Scale, CI = Confidence interval, SD: Standard deviation
Figure 17: Effective rate of adverse reactions of the two groups, CI = Confidence interval, SD: Standard deviation Discussion This study evaluated the efficacy of EA combined with conventional antipsychotic drugs in the treatment of SZ compared with drug therapy alone through eight outcomes. The clinical total effective rate and PANSS score (including general psychopathological score, total score, SAPS score, and SANS score) were treated as major outcomes in this study. The positive symptoms of SZ include delusions, hallucinations, conceptual disorganization, excitement, suspiciousness, grandiosity, and hostility. The negative symptoms include blunted affect, poor rapport, emotional withdrawal, difficulty in abstract thinking, passivity, stereotyped thinking, and lack of spontaneity. Positive, negative, general psychopathology and other symptoms are typically assessed with the PANSS score.[5] This scale is the most commonly used index for evaluating the improvement in SZ symptoms. Similarly, the BPRS score, effective rate of adverse reactions, and significant rate of symptom remission were used as secondary outcomes to evaluate the impact of the intervention on other symptoms.
Major outcomes
This systematic review showed that EA combined with conventional psychiatric drugs in SZ had certain advantages in improving PANSS scale scores, but the degree of improvement was still different for treatment courses. The PANSS total score and positive score of the observation and control groups were not significantly different by the end of 8 weeks of treatment. In addition, there was no significant difference in PANSS general psychopathological score or negative score between two groups after 2 weeks of therapy. Meanwhile, in the 4–6 weeks following treatment, a significant improvement in all four components of the PANSS scores was observed. Accordingly, the improvement in PANSS scale indicators of SZ over the course of 4–6 weeks following EA treatment is more significant, suggesting a greater effectiveness. Electrical stimulation such as Modified Electric Convulsive Therapy (MECT) has been widely used to treat cases of SZ. It is one of the earliest and most effective methods to treat severe mental disorders, and acts by stimulating the brain with a short amount of electric current. Several studies have shown that PANSS scores for SZ patients treated with MECT were statistically significant after 2 or 4 weekends, but not after 12 weekends.[23] Additionally, the effective rate did not increase significantly after 4 MECT treatments, suggesting that the effectiveness of MECT may diminish with prolonged treatment.[24] These results are similar to those of this study. Although electrical stimulation has a therapeutic effect, the human body develops tolerance to stimulation of fixed amplitude and frequency of electrical pulse train, and the stimulation effect will be weakened with time.[25] Unlike MECT, EA involves acupoint stimulation during an awake state. Although EA uses electrical stimulation, it is not limited to this method. Therefore, the duration and course of EA therapy should be considered and changed according to the physiological reaction and symptom improvement of patients in practical application.
WM treatment of SZ can effectively control the disease, but there are still some differences in the efficacy of different antipsychotics, and long-term use of WM has adverse effects on patients' body mass and carbohydrate intake.[26] In the subgroup analysis of this systematic review, risperidone and clozapine were found to be slightly different from other western antipsychotics at improving SAPS positive symptom scores. Risperidone, a common western drug in the treatment of SZ, can alleviate the symptoms of SZ by blocking the midbrain-cortex dopamine and dopamine D2 receptor and can reduce the extrapyramidal adverse reactions caused by excessive blocking of dopamine activity to a certain extent. However, risperidone alone has limited effect on the improvement of symptoms, cognitive, and social functions in SZ patients.[27] Clozapine can block 5-HT support, increase the conversion index of adiponectin, and enhance the antipsychotic effect by promoting the protection of the blocking midbrain system, but the incidence of leukopenia and granulocytopenia caused by clozapine is approximately 10 times higher than that of other antipsychotics,[28] and this adverse reaction may also have an impact on the symptom improvement. Therefore, the combination of EA and WM did not show an advantage in this score improvement, which may be related to the drug characteristics. In terms of improving clinical efficiency, the effect of different WMs combined with electro acupuncture was better than that of drugs alone. Other outcomes measures, which were not subgroup analyzed, showed the same result with a strong association with the effectiveness of EA. Thus, it can be concluded that the total clinical efficacy of EA combined with conventional WM in the treatment of SZ is better than that of drug therapy alone.
Analysis of the other major outcome, total clinical effectiveness, also indicated that EA combined with conventional antipsychotics in the treatment of SZ is superior to that of drug application alone. In Traditional Chinese medicine, SZ is considered as “madness,” and qi, phlegm, blood stasis and fire are the main causes of this disease.[29] EA is a form of acupuncture therapy which can prevent and cure diseases by applying electric current output by electro acupuncture instrument on certain parts of the human body based on the qi obtained by acupuncture with a filiform needle.[30] The current EA treatment for SZ mainly focuses on the Governor vessel of the head, which can not only invigorate Yang Qi, refresh the brain and resuscitate, but also regulates the kidney Qi and nourishes the marrow sea. Modern medical research has confirmed that acupuncture at the scalp projection area of the cerebral cortex can excite the nerve center, establish collateral circulation, improve blood rheology indicators, and enhance the excitability of brain nerve cells, so as to promote the repair of neuronal cells.[31] In addition, the acupuncture points for EA treatment of SZ are mainly DU 20, EX-HN5, EX-HN1. Evidence has shown that the superficial distribution of DU 20 is rich in blood vessels and nerves, such as the greater occipital nerve and the branches of the frontal nerve. The deep layer is the motor area of the cerebral cortex and the paracentral lobules. Acupuncture at DU 20, EX-HN1, EX-HN5 and other acupoints can improve various indexes of the patient's hemorheology and restore brain function to a certain extent.[32],[33],[34] This evaluation also confirms to a certain extent the effectiveness of acupuncture at these parts in the treatment of SZ.
Secondary outcome
The available evidence did not show any differences in the combined use of EA and conventional drugs versus WM alone in terms of the BPRS score in treating SZ. However, this is contrary to the results obtained for the PANSS scale score. This may be related to the fact that the former evaluation only involved only 2 studies, and the conclusions drawn therefrom are insufficient. Similarly, we also did not see any positive effect of EA in the analysis of effective rate of adverse reactions. This may be due to the fact that the effective rate of adverse reactions is a subjective index, and results are easily affected by artificial errors. Therefore, more high-quality studies with larger sample sizes should be included in this conclusion to supplement and improve this research.
Additionally, just as some studies have shown, additional electroconvulsive therapy can quickly relieve the positive symptoms of mental illness.[35] From this meta-analysis, EA in conjunction with WM was shown to relieve symptoms of SZ by the 7th day of treatment quickly, as opposed to day 4 of treatment. Although this conclusion closely echoes the analysis results of the PANSS scale score and assessment of clinical effectiveness response showed above, we were unable to determine the optimal time of treatment to quickly relieve the clinical symptoms of patients since the included studies only provided data on the 4th and 7th day of treatment, and the situation under more treatment courses is unknown. Further understanding of sustainability and its relationship to the overall outcome of the remission needs to be conducted.
ConclusionIn conclusion, our meta-analyses demonstrated that EA combined with conventional antipsychotic drug therapies showed a significant effect in terms of reducing the PANSS scale score, promoting clinical effect, and providing higher symptom relief effective rate in SZ patients when compared with conventional WM alone, although various WMs showed slight differences in the improvement of mental illness evaluation outcome indicators. As EA treatment progressed over the course of 4–6 weeks, various indicators of SZ improved more significantly, suggesting that this may be the best time to combine EA with WM to treat SZ.
Limitations
This study has several limitations which should be addressed. Firstly, several outcomes in this study showed great heterogeneity, which may reflect the different populations and disease course of the subjects in this study, the technique experience of the therapists, and the nature of the treatment chosen for the control group compared with acupuncturist-supervised treatment. Although the PANSS scale score is the most important indicator to evaluate the improvement of mental illness, it still requires objective clinical indicators as an auxiliary evaluation. In addition, most studies did not have a long observation period (<12 weeks), meaning the long-term safety could not be evaluated. In future research, the process of randomization and allocation concealment must be rigorously controlled and described, and more detailed methodologies need to be reported. A detailed description should be given of the data integrity and the methods used to deal with missing data. Finally, because of limitations of the included RCTs, the results of this evaluation need to be verified by increasing sample size and high-quality clinical studies.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
References
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