The Evaluation Of The Integrated Care For Inpatients With Schizophrenia: One-year Randomized Controlled Trial And Follow-up

1.Background Schizophrenia is one of the most severe disorders with heavy human suffering and society expenditure.The psycho-education and psychotherapy have been considered beneficial in clinical and functional outcomes for patients with schizophrenia in long-term therapy with antipsychotics.For example,integrated cognitive remediation reduces negative symptoms;cognitive behavior therapy(CBT)combined with family intervention and social skills training reduce treatment discontinuation and improve life quality in early stage schizophrenia;Cognitive therapy have positive effect on psychiatric symptoms for people with schizophrenia spectrum disorders who have chosen not to take antipsychotic drugs.Recent years,antipsychotics treatment integrated with several components of psychosocial intervention approaches have been developed to deal with several problems(i.e.,psychiatric symptoms,social functioning or rate of relapse)simultaneously in patients with schizophrenia,and have been proved to be more advantageous over traditional medication-alone treatment in terms of effectiveness and efficiency in the treatment of schizophrenia.Over the past twenty years,a few psychosocial interventions developed in the West have been introduced and validated in China: family education module,Community Re-Entry Module(CRM),skill training module and cognitive behavior therapy module.All of them,however,are used mainly in municipal psychiatric hospitals located in big cities such as Beijing,Shanghai,Guangzhou or othermedium-sized cities;most people with schizophrenia live in rural areas in China,and most of them(over 90 %)live with their families who usually work full time.Going to the city every week or very month for therapy always exhaust patients and their caregivers;the transportation and time make the overall cost of the psychosocial intervention much higher.Thus,a relative longtime stay(usually 2 or 3 months)in hospital for each relapse is preferred to ensure satisfactory recovery.Briefly,the long-term regular personal or group psychotherapy at community clinics is not suitable for China's actual conditions.To solve the problem,we designed and evaluated a two-stage model of IT for patients with schizophrenia: a centralized intensive treatment during hospitalization and the following consolidation treatments with long intervals at clinics.In this study,a one-year randomized clinical trial was designed to determine if the two-stage treatment model could be adapted to mental healthcare for patients with schizophrenia.At the stage of intensive treatment during hospitalization,a pharmacotherapy integrated with the CBT and 12-session rehabilitation treatment were conducted to comprehensively address several problems simultaneously in patients with schizophrenia;at the stage of consolidation treatment,patients received a two-hour therapy at psychological clinic every three month,which included medication instruction and consolidation of therapeutic effects of psychosocial intervention.We hypothesized that the two-stage model of integrated treatment would be effective,which would result in lower rate of relapse,alleviation in symptoms and improvement in social outcomes compared with traditional medication-alone treatment.2.Method 2.1.Patients The randomized controlled study was conducted between January 2012 and December 2015 at Guangzhou Huiai hospital,Guangdong Province,South China.All patients,who were diagnosed with the Structured Clinical Interview for DSM-IV(SCID-DSM-IV),were recruited from inpatient psychiatric ward.Patients with diagnoses of schizoaffective or other psychotic disorders were not included.Additional inclusion criteria for participants were aged between 18 and 50 years with education of more than 9 years,and PANSS(Positive and Negative Syndrome Scale)total scores of more than 60.Some potential patients were excluded from this study if they were(a)diagnosed with a serious and unstable medical condition including abuse and/or dependence of alcohol and/or drugs,(b)pregnant or breastfeeding,(c)under a treatment of clozapine with a dose of more than 200 mg/day,or(d)had a treatment of the(modified)electroconvulsive therapy(ECT)within the past six months.Both patient participants and their guarantees gave their written informed consent for participation in this study.The procedures of this study were approved by the Independent Ethics Committee(IEC)of the Guangzhou Huiai Hospital.2.2.Interventions Patients were randomly assigned to IT group or to medication-alone group.Computer-generated random numbers were used to generate two groups.Then,the two groups were randomly assigned to IT and medication-alone.2.2.1.Cognitive behavior therapy In addition to treatment as usual,patients with schizophrenia allocated to the IT group received CBT which focus on alleviation of psychosis symptoms including auditory hallucination and delusions,resolution of emotional problems such as anxiety and depression,boosting self-esteem,and enhancing medication adherence.A maximum of 20-session CBT were offered on a roughly weekly basis for a maximum of 12 weeks(once per week or twice per week)for patients allocated to the IT group.Each session was approximately 45 minutes.Early sessions focused on building a therapeutic alliance,engaging,normalizing and developing explanations for distressing psychotic symptoms.Intensive sessions focus on the construction ofvulnerability–stress formulations and enhancement of coping strategies.2.2.2 Rehabilitation treatment Patients in the IT group and their family members received the rehabilitation treatments which include three modules: medication management,symptom management,and social kill training designed by two principle investigators.Each therapy group consisted of 6 to 8 families.At the stage of intensive treatment(the first 2 months),twelve 120-minute sessions were offered on a weekly basis(one or two sessions per week);at the stage of consolidation treatment,three 120-minute sessions of consolidation treatment were offered at 3-month,6-month and 9-month respectively Medication management module included(a)teaching patients and their family members about the basic knowledge of medication and treatment options to help them see the importance of continuous medication,(b)self-administration and evaluation of medication,(c)identification and dealing with side effects of antipsychotic medication,and(d)asking help from medical staff.Symptom management module included(a)teaching patients and caregivers about the symptoms and course of mental illness to increase their knowledge and understanding of the illness and treatment;(b)developing collaboration with the family,early detection of signs of relapse and coping with persistent symptoms.Social Skills training module was designed to help patients acquire independent living skills and solve social problems to get back to the community.The training included(a)introduction and explanation of skills to be learned in each session,(b)demonstration of the skill by assisted videos,(c)practice by means of role playing and other techniques,(d)learning how to get the skill resources in the real world,(e)practice of skills in the community or places outside the training session,and(f)homework assignments to be conducted by patients with schizophrenia on their own in the natural environments.Psychotherapy and psycho-education were delivered by three therapists whohad at least five years' experience after earning a master degree in clinical psychology or psychiatry.An intensive workshop on training was conducted before the study to ensure that they were proficient in all treatment procedures.Supervision of therapists by regular meetings between therapists and the chief investigator ensured the fidelity to the treatment.CBT were not started for patients until acute episode were controlled.2.2.3 Case management Case management was arranged to enhance continuity in medication and coordination of care for patients of the IT group.In this study,a case management team consisted of at least one nurse,one psychiatrist,one clinical psychologist and one collaborator from community-based mental health services.Each team was responsible for managing 20 to 40 cases.For every month,nurses visited or called the patients and their co-resident family member to assess variation in symptoms,get to know patients' demands,encourage medication adherence and consolidate daily skills training.Then nurses functioned as brokers of services,being contacted by other professionals who were able to deliver the services that patients needed.2.2.4 Pharmacological treatment All patients with schizophrenia were under medication treatment at the baseline.Individualized plan of antipsychotic medication for the patients were determined by psychiatrist who were blind to the group allocation.Mood stabilizers,benzodiazepines and anticholinergic medications were permitted.Medications could be changed at any time during the course of the study if the change was clinically warranted.2.3.Outcome Measures A comprehensive package of measures were conducted for patients at baseline(during hospitalization),and followed up for 3 months,6 months and 12 months at psychological clinic at Guangzhou Huiai Hospital.Study psychiatrists who were blind to group allocation carried out all assessments.2.3.1.Clinical relapse The primary outcome is rate of relapse.Clinical relapse was defined by two levels of assessments.The first level included the following clinical signs:(1)re-hospitalization,(2)an increase in clinic visits because of deteriorated or new developed symptoms,(3)an increase in daily dose or type of joint antipsychotics for controlling the illness,and(4)requiring intensive care to prevent deliberate self-injury or other emergency.The information was provided by caregivers or the doctor's case records.The second level assessment of relapse included measures of two clinical scales:(1)a 25% or more increase in the Positive and Negative Syndrome Scale(PANSS)total scores,and(2)a Clinical Global Impressions(CGI)Scale score of much worse or very much worse.In this study,medication non-adherence was defined as a failure to take medication for one week or longer.2.3.2 Psychiatric symptom and social functioning Secondary outcomes further assessed treatment effectiveness by measuring symptom severity and social functioning(Personal and Social Performance Scale,PSP).PSP are based mainly on the assessment of patient's functioning in four main areas:(1)socially useful activities,(2)personal and social relationships,(3)self-care,and(4)disturbing and aggressive behaviors.The PANSS,CGI-S and PSP have been widely used and have demonstrated validity in studies of schizophrenia populations in China.2.4.Statistical Analyses With 70 participants per group,with a t test at a two-tailed significance of.05,we have over 90% power to detect an effect size of 0.8.We chose a recruitment target of 170(about 85 per group)allowing for a dropout rate of up to 30%(over 80% power to detect an effect size of 0.8).Data were analyzed using SPSS 20.0 software.(1)Independent sample t test,Pearson's chi-square test,or Fisher's exact test were conducted to compare thebaseline characters between the two groups.(2)Time course and treatment differences for changes in the PANSS,CGI and PSP were analyzed using Mixed-Effects Model for Repeated-Measures analyses(MMRM);the effects of treatment,time,and treatment by time interaction with unrestricted covariance of baseline scores were examined.Time was classified into months(baseline,6,9,and 12 months).The null hypothesis was rejected at the level of.05(two-tailed).3.Results A total of 170 patients participated in the research(86 allocated to the IT group and 84 allocated to the medication-alone group respectively).Overall,118 patients(69%)completed the one-year follow-up [62(72%)in the IT group and 56(67%)in the medication-alone group)].3.1.Baseline Characteristics At the baseline,patients of IT group showed more severity in negative symptoms and less severity in personal and social relationships(PSR)scores of PSP than patients of medication-alone group(p = 0.020 and p = 0.038).There was no significant difference in other demographic and clinical characteristics between IT group(age 31.27 ± 8.02)and medication-alone group(age 33.45 ± 8.49).3.2.Rate of Relapse For the primary outcome of rate of clinical relapse,52% of patients in the IT group and 71% of patients in the medication-alone group had relapse.The relapse rate was lower for IT group than medication-alone group(Cramer's V = 0.197,p = 0.012).Rate of re-hospitalization,as one of the indicators of relapse,was specially taken out for analyses.9% of patients in the IT group and 34.5% of patients in the medication-alone group had readmissions to hospital.The rate of re-hospitalization was lower for patients assigned to IT than those to medication-alone treatment(Cramer's V = 0.306,p < 0.001).The difference in mean times(frequency)of re-hospitalization between the IT group(8 times for 8 patients)and themedication-alone group(43 times for 29 patients)was also significant(p = 0.001,Cohen's d = 1.51,95% CI = [0.62,2.40]).Thirty eight percent of patients(65 out of 170)were noncompliant with medication(22.1% of patients in the IT group and 54.8% of patients in the medication-alone group)after 12-month follow-up.The difference between groups in medication noncompliance was significant(Cramer's V = 0.336,p < 0.001).3.3.Changes in Scale Scores For the secondary outcomes,the MMRM analyses were conducted to compare the change in psychiatric symptoms(scores of PANSS and CGI-S)and social functioning(scores of PSP)between IT group and medication-alone treatment group over time.As fixed effects,we entered times and treatment(with interaction term)into the model.As random effects,we had random intercepts for subjects for the effect of treatment.Visual inspection of residual plots did not reveal any obvious deviations from homoscedasticity or normality.The mean scores of baseline,3,6 and 12 months were presented in the Table2 and Table 3.Analyses revealed significant improvement in PANSS total,CGI-S and total PSP scores over one-year follow-up in both groups(all F values > 18.032;all p values< 0.001).At 12-month follow-up,compared to medication-alone group,IT group showed small or moderate changes(improvement)in PANSS and CGI(Cohen's d range from 0.22 to 0.57),and moderate or large improvement in PSP and PSP subscale measures(Cohen's d range from 0.50 to 0.86)(Table 3).Moreover,the change in PANSS total,PANSS positive,PANSS general and CGI-S scores were greater in the IT group than that in the medication-alone group(all F values < 4.303;all p values < 0.005)over time.No significant improvements in PSP total scores(F = 2.219,p = 0.082)was observed over time for the IT group than for the medication-alone group.However,significant improvements in self-care(F = 3.997,p = 0.008)and aggressive behaviors(F = 4.055,p = 0.007)were greater over time for IT group than for medication-alone group.5.Conclusions This study provide evidence that the new two-stage model of integrated treatment was practical and showed better efficacy compared to medications alone in improving overall outcome for patients with schizophrenia.The two-stage IT model is different from the IT treatment models reported in previous studies: It contains a centralized intensive treatment during hospitalization and the following consolidation treatment with relatively long intervals at clinics.The model is particularly informative to countries where medical resources are mainly distributed in developed regions.