| Research BackgroundAntipsychotic drugs are the most effective and commonly used treatment among the guidelines for the treatment of schizophrenia and other mental disorders,which has been widely used around the world at present.However,there are several annoying side effects coming from these antipsychotics,and the patients with schizophrenia and other mental disorders who are taking these antipsychotic drugs are suffering from these side effects in discomfort.The gastrointestinal side effect,such as constipation,is one of the most severe side effects of these antipsychotics drugs,which has been affecting the patients' health and the quality of life severely.Thus the clinicians or the doctors of mental disorders must be quite cautious when they prescribe these drugs for the patients with schizophrenia and other mental disorders and must pay attention to limitations when constipation occur during the usage of antipsychotic drugs.Clozapine and olanzapine are the most commonly used antipsychotics drugs.Constipation caused by antipsychotic drugs could cause severe consequence,which might not only threaten the health of the patients,but might even cause death.The serious complications of constipation caused by antipsychotic drugs include intestinal obstruction,colon obstruction,intestinal ischemia and even perforation,particularly in patients treated with Clozapine and Olanzapine.Evidence show that constipation induced by Clozapine can even potentially cause hepatic venous outflow block and fatal intra abdominal sepsis,which can have a serious impact on the patients'health and life.One study reported that the mortality rate of gastrointestinal hypomotility induced by clozapine is up to about 27.5%.The constipation caused by antipsychotic drugs have a significant impact on quality of patients' life.The pathological and physiological mechanism of constipation caused by antipsychotic drugs remains unclear so far.However,there are various available evidences indicating that the mechanism of constipation caused by antipsychotic drugs might involve the metabolic disorder of serotonin(5-HT),brain derived neurotrophic factor(BDNF),vasoactive intestinal peptide(VIP),gastrin(GAS),or somatostatin.However,at present the available treatments for constipation caused by antipsychotic drugs have their own limitations.Some treatments such as constipation relieving drugs might cause some gastrointestinal discomfort side effects,such as diarrhea,stomachache,abdominal pain and vomiting,affecting the quality of life of patients who were diagnosed with both mental disorders and constipation caused by antipsychotic drugs.The current treatments that help to relieve the constipation caused by antipsychotic drugs generally are unable to meet the needs of most patients.For example,laxatives are the most commonly used drugs for constipation,but the laxatives have only temporary therapeutic effect,and discontinued use might potentially lead to recurrence of constipation caused by antipsychotic drugs.A recent study showed that up to 50%of the patients with constipation are not satisfied with the laxative dependence.Other treatments,such as prokinetic medicine,have serious drawbacks,including a delayed therapeutic response,potential induction of cardiac diseases,and the long-term therapeutic effects is unclear so far.Besides that,there is limited evidence of available treatment for constipation caused by antipsychotic drugs,which make the clinicians or the doctors of both mental disorders and gastrointestinal disease hard to decide which treatment is the best and the most suitable for patients with constipation caused by antipsychotic drugs.Thus,clinical trials with a larger sample size and better experimental design than previous for treating constipation caused by antipsychotic drugs are needed.Previous studies have proved that acupuncture or needle related treatment can help improve the symptoms of chronic constipation,and it is safe to treat patients with fewer side effects.Recent studies have shown that electroacupuncture is significantly more effective to attenuate symptoms in patients with functional constipation than treatment with sham acupuncture.Although there have been literatures proving that electroacupuncture is effective and safe for chronic constipation patients,but there are few studies on the efficacy and safety evaluation of electroacupuncture in the treatment of constipation caused by antipsychotic drugs.Most of the current studies are lack of systematic analysis and have some experimental basis,especially lack of the verification of clinical randomized trial.The therapeutic mechanism of electroacupuncture for constipation caused by antipsychotic drugs remains unknown.However,there are various evidences indicating that the therapeutic mechanism of electroacupuncture for constipation is that electroacupuncture might be treating constipation effectively via improving the metabolic disorder of 5-HT,BDNF,VIP,GAS,or somatostatin.This trial is the first multi center randomized,sham electroacupuncture controlled,single-blinded clinical trial to evaluate the efficacy and safety of electroacupuncture for the constipation caused by antipsychotic drugs.We hope this trial will provide more powerful and more objective evidence-based medical evidence for the electroacupuncture treatment of constipation caused by antipsychotic drugs.At the same time,the patients of constipation caused by antipsychotic drugs and treated by electroacupuncture treatment effectively were studied as subjects.The changes of plasma 5-HT,BDNF,VIP,GAS and somatostatin levels in these patients before and after electroacupuncture treatment were tested.The change of plasma 5-HT,BDNF,VIP,GAS and somatostatin levels were analyzed and discussed to explore the therapeutic mechanism of electroacupuncture treatment for antipsychotic related constipation.We hope this trial will provide more powerful and more objective evidence of mechanism for the electroacupuncture treatment of constipation caused by antipsychotics.Part 1Research ObjectiveThe objective of this study is to evaluate the efficacy and safety of electroacupuncture treatment in patients with constipation caused by antipsychotic drugs.Research MethodsThis study was designed as a multi center,large sample,randomized,single blinded,sham electroacupuncture controlled and clinical trials.The study was conducted in 4 hospitals which was distributed in different regions of China and was selected as the research centers.71 patients with constipation caused by antipsychotic drugs were recruited.7 of them who did not meet the inclusion criteria were excluded,thus 64 of them who met the inclusion criteria were selected and enrolled.The patients who met the inclusion criteria and enrolled were randomly divided into two groups,electroacupuncture group(n=32)and sham electroacupuncture group(n=32).After randomization,the patients of both groups were evaluated for outcome measures at baseline for 2 weeks(baseline period),then the patients of electroacupuncture group received a 24 session treatment of electroacupuncture for 8 weeks(treatment period).The electroacupuncture treatment was needles inserted into the bilateral Tianshu(ST25),Fujie(SP14),and Shangjuxu(ST3 7)acupoints in the puncture depth of approximately 15-25 mm(the abdomen acupoints)and about 15-20 mm(the limb acupoints)with a real current electricity which the intensity of current,which was adjusted to the comfort level of patients'feeling.The patients of sham electroacupuncture group received 24 sessions treatment of sham electroacupuncture for 8 weeks(treatment period).The sham electroacupuncture treatment was given needles inserted in the depth of about 2-3 mm superficially(both the abdomen and limb acupoints)into the bilateral sham ST25,sham SP14 and sham ST37,which were located on the 2 cm lateral to the acupoints of the electroacupuncture treatment,but without electricity.Both the electroacupuncture and sham electroacupuncture treatment was 30 minutes per session,3 sessions a week.After treatment period,the patients of both groups were followed up for 8 weeks(follow up period).The outcome measure were observed and recorded during the whole period(includes the baseline period,treatment period,and follow up period)to evaluate the efficacy and safety of electroacupuncture/sham electroacupuncture.Outcome MeasuresThe change in complete spontaneous bowel movements(CSBMs)was used as primary outcome.The change in CSBMs refers to the mean weekly CSBMs of treatment period(8 weeks)or follow-up period(8 weeks)minus the mean weekly CSBMs of baseline(2 weeks).All defecation conditions of participants were recorded by research assistants.CSBM is defined as the complete defecation occurring without the help of any medicine or other assistant method in the previous 24 hours.Secondary outcomes include change in spontaneous bowel movements(SBMs),decrease in frequency of rescue measures,as well as decrease in the Patient Assessment of Constipation Quality of Life(PAC-QOL)score,Brief Psychiatric Rating Scale(BPRS)score and Treatment Emergent Symptom Scale(TESS)score.SBMs is defined as a complete or incomplete defecation occurring without the help of any medicine or other assistant method in the previous 24 hours.The rescue measure was an enema used for participants who had no defecation for 3 or more days.The PAC-QOL score was used to evaluate satisfaction and life quality of constipated patients where in higher scores reflected greater impairment or dissatisfaction.BPRS score is used to measure psychiatric symptoms of mental disorders.TESS score is commonly used to evaluate adverse effects caused by antipsychotic drugs.Research assistants helped participants finish the PAC-QOL at baseline,8th week(the last week of treatment period)and 16th week(the last week of follow-up period).BPRS and TESS were evaluated at baseline and 8th week.A blinding test was conducted in treatment week 4 and week 8:Participants were asked whether he/she knew the treatment was electroacupuncture or sham electroacupuncture or unknown.Statistical Methods:Intention-to-treat(ITT)principle was used in the whole analysis.SPSS 20.0 was used for statistical analysis of all data.“Multiple imputation”approach was used to impute the missing data(n=3).Analysis of covariance with baseline and sites as covariates was used for changes of mean weekly CSBMs,mean weekly SBM,mean weekly frequency of rescue measures and changes of PAC-QOL score,BPRS score and TESS score from baseline between two groups.Repeated measures analysis of variance with baseline and sites as covariates was used to analyze the difference between baseline,treatment period and follow-up period data of mean weekly CSBMs,mean weekly SBM,mean weekly frequency of rescue measures and scores of PAC-QOL in electroacupuncture or sham electroacupuncture groups.For baseline characteristics,a T-test was used for continuous variables which followed normal distribution;otherwise,Wilcoxon rank sum test was used appropriately.Chi-squared test or Fisher's Exact Test was utilized for categorical variables.The success of blinding was analyzed with Chi-square tests by comparing the proportions of participants who guessed they had received electroacupuncture between groups.A 2-sided test was used in all tests with P<0.05 as the significance level.Results:One patient in the electroacupuncture group withdrew from the trial due to mild subcutaneous hematoma during electroacupuncture treatment,and two patients of sham electroacupuncture group discontinued the treatment without any reason given.The missing data(n=3)was imputed using‘multiple imputation' approach.There was no difference between two groups in age,gender,antipsychotics,mean CSBMs per week,mean SBMs per week,frequency of enema used per weeks,BPRS score.For PAC-QOL and TESS scores,the electroacupuncture group was slightly higher,but not significantly than the sham electroacupuncture group.Both groups presented an increasing trend in weekly CSBMs during trials.The mean weekly CSBMs of the treatment and follow-up period of electroacupuncture group was 1.59±1.06(mean±standard deviation,the same as below)and 1.90±1.03,while of sham electroacupuncture group was 1.15±0.85 and 0.88±0.71,respectively.The mean weekly CSBMs of each group during the treatment and follow-up periods showed improvement compared to the baseline,by Bonferroni pairwise comparisons of repeated measures analysis of variance.The increases in CSBMs per week of electroacupuncture group during treatment period and follow-up period were 1.37±1.07 and 1.66±1.11,while of sham electroacupuncture group were 0.89±0.65 and 0.60±0.56,respectively.The electroacupuncture group showed higher increase in CSBMs per week when compared with the sham electroacupuncture group during both the treatment period(P=0.029,partial eta square(? 2)=0.081)and followup period(P<0.001,? 2=0.323,by analysis of covariance with the baseline CSBMs and si te as covariates).The mean weekly SBMs of each group during both experimental periods showed improvement when compared to the baseline,by pairwise comparisons of repeated measures analysis of variance.There was significantly difference between the electroacupuncture and sham electroacupuncture groups in increase in SBMs per week of the treatment period(P=003,? 2=0.141)and follow-up period(P<0.001,? 2=0.271,by analysis of covariance with the baseline SBMs and sites as covariates).The mean weekly frequency of enema uses for each group during treatment and follow-up periods showed significant decrease when compared to the baseline,by pairwise comparisons of repeated measures analysis of variance.There was a significant difference between the electroacupuncture and sham electroacupuncture groups in decrease in frequency of enema uses per week in the treatment period(P=0.018,?2=0.090)and follow-up period(P<0.001,?2=0.193,by analysis of covariance with the baseline weekly frequency of enema uses and sites as covariates).The decrease in PAC-QOL Score showed significantly difference between the electroacupuncture and sham electroacupuncture group in both Week 8(P=0.006,?2=0.121)and Week 16(P=0.002,?2=0.150,by analysis of covariance with the baseline PACQOL score and sites as covariates).No significant difference was found between the two groups neither in change of the scores nor between the baseline and 8th week in BPRS and TESS scores.As for adverse event,only one patient of the electroacupuncture group reported a subcutaneous hematoma which was mild and transient.As for blinding assessment,the proportion of electroacupuncture group participants who guessed that they received electroacupuncture at week 4,week 8,and both weeks 4 and 8 were 80.65%,74.19%and 74.19%respectively,and of SEA group were 73.33%,66.67%and 66.67%respectively.No statistical difference was found in blinding assessment between the two groups.ConclusionsThe results of this study showed that:(1)Both electroacupuncture and sham electroacupuncture treatments increased the CSBMs and SBMs,reduced the rescue measures used for constipation relief,and improved the overall quality of life for patients with constipation caused by antipsychotic drugs in treatment period and follow-up period;(2)Electroacupuncture appeared to have better efficacy than sham electroacupuncture in increasing CSBMs and SBMs,reducing rescue measures and decreasing PAC-QOL scores,especially during the follow-up period;(3)Electroacupuncture appeared to be efficacious and safe,have a sustained effect in the follow-up period,and show superiority to sham electroacupuncture on patients with constipation caused by antipsychotic drugs in this study.More studies are required for further exploration of the mechanisms underlying this treatment.Part 2Research Objective:this study is based on the previous clinical trials.The patients of antipsychotic related constipation who were treated by electroacupuncture treatment effectively were studied as subjects.The changes of plasma 5-HT,BDNF,VIP,GAS and somatostatin levels in these patients before and after electroacupuncture treatment were tested.The change of plasma 5-HT,BDNF,VIP,GAS and somatostatin levels were analyzed and discussed to explore the therapeutic mechanism of electroacupuncture treatment for antipsychotic related constipation.We hope this trial will provide more powerful and more objective evidence of mechanism for the electroacupuncture treatment of constipation caused by antipsychotics.Research MethodsThe subjects of this study were from the first part of the clinical trial,who were of electroacupuncture group and diagnosed with antipsychotic related constipation and have been treated by electroacupuncture treatment effectively.All the subjects in this part were willing to donate their blood samples for mechanism research before and after electroacupuncture treatment with informed consents.The definition of having been treated by electroacupuncture treatment effectively was that the CSBMs per week value increased by>1 per week on average compared with the baseline during the treatment period and the follow-up period.The expressions of plasma 5-HT,BDNF,somatostatin,VIP and GAS in patients with constipation caused by antipsychotics before and after electroacupuncture treatment were tested.Blood samples were collected with heparin sodium anticoagulant tubes in the morning before eating breakfast prior to the first session of electroacupuncture treatment and at the 8th week after last session of electroacupuncture treatment.Then the blood samples were separated to plasma with standard operation of plasma separation.After that the plasma was marked with number and stored in the-80 degree refrigerator.BDNF expression of plasma was tested by double antibody sandwich ELISA.GAS,somatostatin,5-HT,VIP expression of plasma were tested by competitive ELISA.Paired t test was used to statistically analyze the differences and trends of plasma 5-ht,BDNF,somatostatin,VIP and GAS levels before and after electroacupuncture treatment.Research ResultsThere were total 21 patients who were diagnosed with constipation caused by antipsychotic drugs,treated with electroacupuncture treatment effectively and were willing to donate their blood samples before and after electroacupuncture treatment.The collected number of blood samples was 42.However,there were 4 blood samples of two patients collected before and after treatment could not be used to test and analyze.Thus there were total 38 blood samples of 19 patients which can be used to test and analyze.Among them,there were 9 patients who were diagnosed with constipation caused by clozapine and 10 patients diagnosed with constipation caused by olanzapine.The plasma 5-HT,GAS,somatostatin,5-HT,VIP levels before and after electroacupuncture treatment of the 38 the blood samples were tested and statistically analyzed.The results of statistical analysis were as follows:(1)There was no significant difference in plasma 5-HT levels before and after treatment in 9 patients who were diagnosed with constipation caused by clozapine(434.09±137.97 pg/ml before treatment vs 469.87±203.31 pg/ml after treatment,P=0.636);There was significant difference in plasma 5-HT levels before and after treatment in 10 patients who were diagnosed with constipation caused by olanzapine,the plasma 5-HT level after electroacupuncture treatment was lower than that before treatment(447.90±97.73 pg/ml before treatment vs 347.34±74.28 pg/ml after treatment,P=0.005).(2)There was significant difference in plasma BDNF levels before and after treatment to 9 patients who were diagnosed with constipation caused by clozapine,the plasma BDNF level after electroacupuncture treatment was higher than that before treatment(299.46±129.05 pg/ml before treatment vs.525.66±251.51 pg/ml after treatment,P=0.028);There was significant difference in plasma BDNF levels before and after treatment in 10 patients who were diagnosed with constipation caused by olanzapine,the plasma BDNF level after electroacupuncture treatment was higher than that before treatment(304.89±205.15 pg/ml before treatment vs.421.42±195.02 pg/ml after treatment,P=0.036).(3)There was no statistical difference in plasma somatostatin levels before and after electroacupuncture treatment in 9 patients diagnosed with constipation caused by clozapine(57.51±22.15 pg/ml before treatment vs.65.70±18.79 pg/ml after treatment,P=0.375);There was no statistical difference in plasma somatostatin levels before and after electroacupuncture treatment in 10 patients diagnosed with constipation caused by olanzapine(60.66±10.03 pg/ml before treatment vs.63.29±15.50 after treatment,P=0.640).(4)There was no statistical difference in plasma GAS levels before and after electroacupuncture treatment in 9 patients diagnosed with constipation caused by clozapine(132.61±22.12 pg/ml before treatment vs.163.48±42.70 pg/ml after treatment,P=0.090);There was statistically significant difference in plasma GAS levels before and after electroacupuncture treatment in 10 patients diagnosed with constipation caused by olanzapine,the plasma GAS level after treatment was lower than that before treatment(170.63±30.63 pg/ml before treatment vs.144.10±16.31 pg/ml after treatment P=0.016).(5)There was no statistical difference in plasma VIP levels between pretreatment and post-treatment in 9 patients diagnosed with constipation caused by clozapine(36.71 ±7.29 pg/ml before treatment vs 30.73± 10.05 pg/ml after treatment,P=0.089);There was no statistical difference in plasma VIP levels in 10 patients wi th constipation caused by olanzapine before and after electroacupuncture(24.79±6.76 pg/ml before treatment vs.21.23 ± 5.95 pg/ml after treatment,P=0.177).Conclusions(1)Electroacupuncture improves plasma BDNF levels in patients with constipation caused by clozapine while improving constipation caused by clozapine.BDNF has been shown to promote intestinal motility in some medical evidences.This suggests that electroacupuncture might promote intestinal motility by increasing plasma BDNF levels to attenuate constipation symptoms,which might be one of the mechanisms of electroacupuncture efficacy for constipation caused by clozapine.(2)Electroacupuncture improved the symptoms of constipation in patients who were diagnosed with constipation caused by olanzapine.At the same time,plasma 5-HT and GAS levels of the patients with constipation caused by olanzapine were decreased,and plasma BDNF levels were increased after electroacupuncture sessions.This indicates that the decrease of plasma 5HT and GAS levelsand the increase of plasma BDNF levels in patients with constipation caused by olanzapine might be the mechanisms of electroacupuncture treatment efficacy for constipation caused by olanzapine.(3)The results of this study suggest that plasma BDNF levels might be used as a blood indicator for the improvement of constipation caused by clozapine.BNDF might be used as a biomarker for constipation caused by clozapine treated with electroacupuncture,drugs or other therapies effectively;plasma BDNF levels,plasma 5-HT and GAS levels might be used as a blood indicator for the improvement of constipation caused by olanzapine,and used as a biomarker for constipation caused by olanzapine and treated with electroacupuncture,drugs or other therapies effectively.The study protocol was approved by the ethics committees of 4 research hospitals and has registered in the Chinese Clinical Trial Register(ChiCTR,ChiCTR-ONC-17010842,Registered 11 March,2017)... |
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