| Tic disorder(TD)is a common neuropsychiatric disease in childhood.The prevalence of TD is increasing year by year,and it is often accompanied by one or more comorbid diseases.Pharmacotherapy is the main treatment to control the symptoms of TD in children,but there are many problems,such as big differences among medication choices,common adverse drug reactions,medication choices without considering the needs of patients,poor medication compliance and so on.Therefore,the pharmacotherapy of children with TD still needs to be standardized.The clinical medication path and medication adherence management is an important way to standardize the treatment process and promote rational drug use,but there are no clinical western medicine treatment pathways and medication adherence management strategies for children with TD in the worldwide.Study aimBased on evidence from secondary research and observational research,we aimed to construct and verify the clinical medication path and medication adherence management strategies for children with TD,and provide reference for promoting the rational drug use.Study methodsThis study was divided into three parts.First sub-study:Evidence-based evaluation of clinical evidence of TD in children;Second sub-study:The choice and needs,medication adherence,effectiveness,safety and cost effectiveness of clinical medication use of TD in children;Third sub-study:Construction and verification of clinical medication pathways and medication adherence management strategies.First sub-study:Evidence-based evaluation of clinical evidence of TD in children.(1)We used expert consultation to formulate the framework of clinical medication path and medication adherence management strategies.We established a multidisciplinary expert team,including pediatric neurologists,nurses,pharmacists,evidence-based methodologies and medical record management experts.Then the framework was formulated including participants of the clinical medication management,TD assessment,comorbidity assessment,treatment goals and plans,medication treatment for tics,and medication treatment for comorbid ADHD,recurrence and referral management,medication adherence management.(2)Guideline evaluation and overview of systematic reviews of the efficacy and safety of drug treatment for TD.A comprehensive search of GIN and NGC guideline databases,Cochrane Library,Medline,EMBASE,CBM,CNKI and other literature databases was conducted to include clinical practice guidelines and systematic reviews of the effectiveness and safety of drug treatment for TD.AGREE II and AMSTAR-2 tools were used to evaluate the quality of included studies and obtained the information in various aspects in the clinical medication pathways and medication adherence management strategies.The intervention measures,control group,outcome measurement and effect sizes of meta-analysis of different drug treatment were also extracted.Second sub-study:We used observational research to evaluate the TD clinical medication selection and needs,adherence,efficacy,safety and cost effectiveness of commonly used drugs.(1)Study population:① The population for the survey on doctors and patients’medication choice:242 pediatric clinicians from hospitals all over China where members of the Child Developmental Behavior Group of the Pediatric Branch of the Chinese Medical Association belong were included from February 2020 to March 2020.And a sequential collection of 610 children with TD from the outpatient department of West China Second Hospital of Sichuan University and Chengdu Women and Children’s Hospital were included from January 2018 to December 2019.② Followup study population:Based on the above-mentioned cross-sectional study,we selected patients who were taking medication,and established a follow-up cohort for the evaluation of medication adherence and efficacy and safety of commonly used drugs for children with TD in the southwest region("Southwestern TD Cohort").(2)Research content:① We conducted a cross-sectional study to collect information of clinicians’medical behavior,medication choice and related factors,the guardian’s knowledge of diseases,medical treatment behavior,medication choice and demand.We used x±s or median/interquartile range,frequency/composition ratio to describe the data.②Based on the "Southwestern TD Cohort",we designed a questionnaire referred to the protection motivation theory and assessed the medication adherence using Morisky scale.We used exploratory factor analysis and Cronbach’s coefficient to evaluate the structural validity and reliability,and established a structural equation model and carried out path analysis and mediation effect testing to explore the influencing factors of medication adherence,using the maximum likelihood method to estimate the model.According to the relationship between various variables,we designed medication adherence management strategies based on the protection motivation theory.③We included TD patients who were taking clonidine,tiapride+clonidine,and tiapride from the "Southwestern TD Cohort".Prospective cohort study was designed to evaluate the efficacy and safety of these three drugs in the treatment of TD.We conducted follow up in 4-48 weeks after drug treatment using YGTSS scale.Full analysis set,per-protocol set and safety set were used for data analysis,and a multi-level analysis model of repeated measurement data was used to evaluate the efficacy.④We used decision tree model simulation method to evaluate the cost effectiveness of tiapride,clonidine transdermal patch,aripiprazole,tiapride combined with clonidine transdermal patch.Based on the recommendation from guidelines and clinical expert opinions,we built a 1-year decision tree model,and the effective rate was used as the outcome measurement,and the cost mainly included direct costs and indirect costs.We conducted one-dimensional linear sensitivity analysis and probability sensitivity analysis.Third sub-study:Construction and verification of clinical medication pathways and medication adherence management strategies.(1)Based on the results of the first two parts,we followed the process of clinical medication path construction and adopted the improved Delphi expert consultation method to form the first draft of TD clinical medication path and medication adherence management strategies,GRADE tool was used to assess the quality and recommendation of the evidence.(2)We designed prospective non-randomized experimental study to evaluate the implementation effects of clinical medication pathways and medication adherence management strategies for children with TD.100 participants were included.The intervention group and the control group were matched 1:1 according to age,gender,and comorbidities.There were 50 patients in each group,and the patients in the intervention group received standardized medication route management,patients in the control group received the routine procedures.We conducted follow-up of treatment effect,adherence and satisfaction after 12 weeks treatment.The YGTSS scale was used to evaluate the treatment effect,and the Morisky scale was used to evaluate medication adherence.The YGTSS score reduction rate>30%was defined as effective.Logistics regression was used to analyze the differences in drug efficacy of different intervention groups,and the repeated measures mixed-effects model was used to compare the differences in medication adherence scores between the two groups.Study resultsFirst sub-study:Finally,5 guidelines and 27 systematic reviews were included.The recommendation showed that risperidone,aripiprazole,clonidine and guanfacine were strongly recommended;Tiapride was recommended as C-level in the USA guidelines and as first-line drug recommendation in China.Evidences for "participants of clinical medication path","treatment goals and plans","relapse and referral management",and"medication adherence management" were scarce.Meta-analysis showed that although typical psychiatric drugs could control tic symptoms,but their safety was not good;risperidone,aripiprazole,clonidine and tiapride had good efficacy and safety,and the research evidence was relatively sufficient;Clonidine could effectively control tic symptoms with fewer adverse reactions,especially for patients with ADHD;Tomoxetine and methylphenidate could significantly improve tic symptoms of TD patients with ADHD.Second sub-study:(1)We collected 242 questionnaires for medication selection survey from doctors from 24 provinces in China.For TD patients without comorbidities,the priority orders of treatment drugs were tiapride(60.74%),clonidine(32.64%)and haloperidol(25.62%),aripiprazole(16.53%)and sulpiride(12.4%).For TD patients with ADHD,the priority orders of treatment drugs were tiapride(50.83%),clonidine(32.64%),haloperidol(25.21%),tomoxetine(25.21%)and aripiprazole(21.49%).The priority factors when choosing drugs included:recommended by clinical guidelines(4.55 scores),better clinical efficacy(4.44 scores),better safety(4.38 scores),sufficient clinical research evidence(4.24 scores),and higher degree acceptance of drug formulations(4.11 scores)and better patient adherence with medication(4.1 scores).A total of 610 questionnaires for TD patients were collected.67.4%guardians thought it was necessary to take the medicine on time and in accordance with the prescribed dosage,23.6%thought that the medicine could be stopped or reduced if the symptoms were relieved.The priority factors were ranked as follows:fewer adverse reactions(4.52 scores),doctor’s recommendation(4.44 scores),better clinical efficacy(4.29 scores),smaller drug dosages(4.27 scores),more convenient dosage forms(4.01 scores),and more adequate supplies in hospital(3.95 scores).(2)A total of 317 patients with TD were included for the adherence evaluation,the mean age was 8.38±2.54 years,and the mean course of disease was 3.19±2.46 years.The medication adherence scores,of showed 15.1%low adherence,37.6%moderate adherence,and 47.3%high adherence with an average of 5.70±1.685.Multivariate linear regression analysis showed that four factors were related to adherence:comorbidities(β=0.124;SE=0.167;P=0.011),education level of the main guardian(β=0.236;SE=0.110;P<0.001),quality of life(β=0.399;SE=0.112;P<0.001)and the types of drugs taken(β=0.166;SE=0.047;P=0.001).Structural equation model analysis showed:severity(β=0.295,95%CI:0.103～0.493),external return(β=0.326,95%CI:0.200～0.446),self-efficacy(β=0.200,95%CI:0.057～0.353),susceptibility(β=0.220,95%CI:0.084～0.352)and quality of life(β=0.353,95%CI:0.211～0.500)have a direct positive impact on the adherence of TD patients.Quality of life mediated between external returns and adherence variables(effect size 13.9%).Based on the above research results,medication adherence management strategies were designed from four aspects:increasing severity and susceptibility,weakening external returns,and increasing self-efficacy.(3)We included a total of 312 TD patients for efficacy and safety evaluation,the mean age was 8.32±2.54 years and the mean course of disease was 1.95±1.72 years.The total YGTSS scores of tiapride group,clonidine group,tiapride combined with clonidine group at baseline were 20.37±8.75,22.55±10.79,and 20.72±10.49,the total YGTSS scores decreased after treatment.During the 12-week visit,the mean changes from the baseline were-12.05,-8.95,and-9.00,respectively,and the differences were statistically significant.,The pairwise comparison between the three groups after adjusting the P value by Bonferroni method showed that tiapride combined with clonidine could significantly showed a better reduction of YGTSS scores than tiapride group(P<0.0167)and clonidine group(P<0.0167),there was no statistically significant difference between tiapride group and clonidine group(P>0.0167).There was no statistically significant difference in the incidence of ADR among the three groups.(4)The cost of clonidine transdermal patches was higher than tiapride,but the effect was better than tiapride,the cost-effectiveness ratio was 9,315.33 yuan,and the incremental cost-effectiveness ratio was 13,407,143.696 yuan.Clonidine was not economical according to the standard of willingness to pay(212,175 yuan).Aripiprazole,tiapride combined with clonidine transdermal patch therapy were inferior treatment.Sensitivity analysis showed that the results were robust.Third sub-study:A total of 26 experts from medical institutions in Sichuan Province were included.After two rounds of Delphi expert consultation,the clinical medication path and medication adherence management strategies for children with TD patients were constructed.There were 8 categories with 41 items,including participants of the clinical medication management,TD assessment,comorbidity assessment,treatment goals and plans,medication treatment for tics,and medication treatment for comorbid ADHD,recurrence and referral management,medication adherence management.A prospective non-randomized experimental study included a total of 100 children with TD.The results showed that the improvement in drug treatment effect,adherence and satisfaction in the group of the clinical medication path and medication adherence management strategies group was significantly better than these in the conventional medication group(P<0.05).Study conclusions(1)Based on the evidence of secondary research and observational research,combined with the experience of clinicians,patients and guardians’ opinions,we have constructed the clinical medication path and medication adherence management strategies for children with TD,which could significantly improve patient treatment outcome,adherence and satisfaction.(2)It is recommended that pediatricians in medical institutions at all levels to manage the medication adherence of patients with TD from the severity,susceptibility,external returns,and self-efficacy,so as to improve patients and guardians’ awareness of the severity and susceptibility of disease and medication non-adherence,weaken external returns and increase self-efficacy,and ultimately improve medication adherence.(3)This study actively explored the clinical medication pathways and medication compliance management strategies for children with TD in China.Compared with the clinical practice guidelines,the research results added more contents,such as participants of the clinical medication management,treatment goals and plans,recurrence and referral management and medication adherence management,it provided a standardized and highly operable medication path reference for the clinical practice of TD,so it is expected to be widely used in the treatment practices for children with TD.In addition,this study also provided a methodological reference for the formulation of drug management strategies for other complex childhood chronic diseases.(4)It is suggested that future research should update and improve the clinical medication path and medication adherence management strategies using the latest evidence-based medicine research evidence. |
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