Cost-effectiveness analysis of psychosocial intervention for early stage schizophrenia in China: a randomized, one-year study

Background A combination of psychosocial interventions and medications has been highly recommended as a successful treatment package for schizophrenia. Its cost-effectiveness has not been fully explored yet. The aim of the present analysis was to evaluate the cost-effectiveness of antipsychotics combined with psychosocial treatment and treatment as usual for patients with early-stage schizophrenia. Method Patients with schizophrenia (N = 1, 268) were assigned to the combination of medication and psychosocial intervention or treatment as usual for up to 12 months. Cost analysis included direct medical costs, direct nonmedical costs and indirect costs. Quality-adjusted life year (QALY) ratings were assessed with Short- Form 6D. Results Average monthly psychosocial intervention costs for combined treatment were higher than treatment as usual (p = 0.005), but no significant differences were found in direct costs, indirect costs, and total costs between two groups (all p-values ≥ 0.556). Combined treatment was associated with significant higher QALY ratings than treatment as usual (p = 0.039). Compared with treatment as usual, combined treatment resulted in a gain of 0.031 QALY ratings at an additional cost of US$ 56.4, yielding an incremental cost-effectiveness ratio of US$ 1819.4 per QALY gained. Conclusions Despite some limitations, our results supported that medication combined with psychosocial treatment was more cost-effective than treatment as usual for patients with early-stage schizophrenia. Trial registration clinicaltrials.gov Identifier: NCT00654576 Electronic supplementary material The online version of this article (doi:10.1186/s12888-014-0212-0) contains supplementary material, which is available to authorized users.


Introduction
Long-term treatment effectiveness has remained a major problem for schizophrenic patients. Pharmacotherapy alone is insufficient to prevent relapses or to ensure recovery of functional disabilities in the illness course.
In an attempt to improve the long-term outcome for individuals with schizophrenia, there is growing interest in psychosocial interventions as an adjunct to facilitate recovery from an initial episode of psychosis and reducing the long-term disability resulted from schizophrenia.

Objectives
The primary objective is to evaluate rate of treatment discontinuation and time to treatment discontinuation comparing combined treatment and medication treatment alone.
The secondary objectives are to assess: changes of psychopathology in schizophrenia, side effects, subjective attitudes toward medication, social function and cognitive function, quality of life, family/carer burden, and cost-effective analysis.

Study design
The study is a multicenter, randomized and controlled study with an intervention period of 1 year and assessments of participants at baseline, 3, 6 months and every 3 months thereafter. An additional visit will be paid in case of discontinuing and/or changing medication, hospitalization and/or relapse (for definitions see below). The 10 clinical sites is the Second Xiangya Hospital, Chongqing Mental Health Center, Psychiatric Hospital of Jiangxi Province, West China Hospital, Mental Hospital of Henan Province, Beijing Anding Hospital, Shanghai Mental Health Center, Guangzhou Brain Hospital, Hunan Brain Hospital, and Nanjing Brain Hospital in China. Participants will be randomly assigned to receive the combination of medication and psychosocial treatment or medication alone and are monitored for up to 12 months or until medication treatment is discontinued for any reason after baseline assessment. Group assignment is based on a 1:1 randomization scheme balanced by sites and medication prescribed by independent investigator according to a computer generated randomization list.

Study population
The study will enroll approximately 1,300-1400 subjects with schizophrenia, who are randomly distributed to receive antipsychotic drugs combined with psychosocial intervention or antipsychotic drugs alone based.
The sample sizes are selected to make possible the detection of a 15 percent difference in discontinuation rates after one year with 85 percent power and a two-tailed alpha level of significance of 0.05.

Inclusion criteria
All patients are enrolled from outpatient psychiatric clinics and under maintenance treatment. Eligible patients are 16 to 50 years of age who have to meet following enrollment criteria:  DSM-IV diagnosis of schizophrenia or schizophreniform disorder within the past five years, as determined by the Structured Clinical Interview of the Diagnosis (SCID) administered by study investigators or trained staff;  living with family members who could be involved in the patient's care;  PANSS (Positive and Negative Syndrome Scale) total scores are ≤60;  on maintenance treatment with one of the following 7 oral antipsychotics: chlorpromazine, sulpiride, clozapine, risperidone, olanzapine, quetiapine or aripiprazole.
We select these 7 antipsychotics because over 90% of schizophrenia patients in China are prescribed one of these antipsychotics.

Exclusion criteria
 Patients are excluded if they are:  prescribed two or more antipsychotics or long-acting injectable antipsychotics;  participating in other therapy programs;  pregnant or breastfeeding;  a serious and unstable medical condition.

Pharmacotherapy
Because all patients are on maintenance treatment, we encourage clinicians to try to keep patients on the same medication for at least 3-6 months in order to gauge treatment efficacy and minimize early discontinuation. However, medications could be changed at any time during the course of the study if the change is clinically warranted. If a patient's medication is stopped or switched, patients are classified as discontinued and terminated from the study. No further assessments will be required for these patients.

Concomitant medication
Mood stabilizers, benzodiazepines, antidepressants, and anticholinergic medications are permitted, and daily doses of all medications are recorded throughout the study.

Brief intervention
In medication alone group, the brief intervention will also be given to paitents, which included case management with antipsychotic medication and supportive interventions, which are provided monthly for 12 months.

Psychosocial intervention
Patients will be assigned to the combined treatment group received medication treatment and are enrolled in a psychosocial intervention program.
The psychosocial intervention strictly followed a detailed treatment manual designed by the principal investigators and included four evidence-based practices: psycho-education, family intervention, skills training and cognitive-behavioral therapy. Psychosocial intervention participants are seen 12 times (once per month for 12 months), receiving each of the four group treatments on the same day, for a total of 48 one-hour sessions (see Table 1 for topics covered). A lunch break and two half-hour breaks are provided to maintain engagement and attention. We have designed this comprehensive psychosocial intervention to be delivered on the same day once a month mainly due to the care structure in China, the potential time and cost burden to patients and their family members, as well as feasibility of being adopted by other care settings. In China, the vast majority of schizophrenia patients live with their family members because of limited social welfare for severe mentally ill patients. Many of these family members also work full time so it is not convenient for them to take time off every week and bring the patients for Treatment fidelity is maintained by having the therapists' supervisors assess adherence to the treatment manual after each monthly session by reviewing videotapes.

Outcome measures
All subjects are assessed monthly by the study psychiatrists and every 2 weeks by a research assistant who had instructions to contact the psychiatrist if medication discontinuation, relapse or other problems are suspected. The psychiatrists assess patients mainly for medication management purposes, evaluating for clinical response to medications, medication compliance, and major side effects. The research assistants assess patients, patients' caregivers, and other sources every two weeks by phone for any hospitalizations, relapses, or other causes of treatment discontinuation. The research assistants also administer the symptom and functioning rating scales at scheduled intervals.
The primary measure is rate of treatment discontinuation or change and time to treatment discontinuation. Once a patient discontinued the study, no further assessments are completed. Treatment discontinuation criteria:  clinical relapse/hospital admission;  lost to follow-up or patient's refusal;  noncompliance, defined as taking less than 70% of prescribed medications, detected either by the treating psychiatrist or research assistants during follow-up assessments;  changing or stopping of initial antipsychotic by doctor or patient request  intolerability, defined as severe side effects that caused the treating psychiatrists to stop the medications.
Clinical relapse is defined by any one of the following:  psychiatric hospitalization;  an increase in the level of psychiatric care (e.g., from clinic visits to day treatment) and a 25% or more increase in the PANSS total score (or 10 points if the initial score is 40 or less);  a Clinical Global Impressions (CGI) Scale score of "much worse" or "very much worse";  deliberate self-injury;  emergence of clinically significant suicidal or homicidal ideation;  violent behavior resulting in significant injury to another person or significant property damage.  (Wechsler, 1987). This is a test of memory for nonverbal stimuli measuring visuomotor speed. For this protocol, the outcome measure is immediate delayed memory raw scores.
 Wechsler Adult Intelligence Scale-Revised Digit Symbol Test (Wechsler, 1981). This is a test of psychomotor speed and attention, in which the participant is allowed 120 seconds to move through a grid of 133 numbers (1 to 9) and pair them with the correct symbol by using a key consisting of nine symbol-digit pairs. The outcome measure is the number of correct symbols drawn within 120 seconds.
 Computerized Wisconsin Card Sorting Test (128-card version) (Heaton et al.,1993). This is a commonly used test of executive functioning, measuring cognitive flexibility, maintenance of a cognitive set, and working memory. In this test, the outcome measures are the number of categories completed and the number of perseverative errors made.
 Trail Making Tests, Part A and B (Reitan and Wolfson.,1993). In Part A, subjects draw lines connecting circles that are numbered.
In Part B, subjects connect circles by alternating between ascending numbers and letters in alphabetical order. The outcomes measures are the time to complete the tests. (Wechsler,1981). Subjects are given sets of digits to repeat initially forwards then backwards. The number of correctly recalled trials is counted for forward and backward span.  Safety measures. The physical examination is recorded regularly.

 Wechsler Adult Intelligence Scale-Revised Digit-span Task Test
The Treatment Emergent Symptom Scale is used for monitoring adverse effects.

Statistical Methods and Analytic Plan
Analyses will be performed according to the intention-to-treat principle.
Randomized patients who have at least one assessment during treatment made up the intention-to-treat population. Descriptive statistics will be provided for all data broken down by treatment group, by visit and by site. Continuous variables will be described by mean, standard deviation, range and number of observations. Discrete variables will be described by frequencies and percentages. All statistical tests will be carried out as two tailed tests; and alpha (level of significance) is set at 5%. Differences in continuous variables will be tested with analysis of variance, with treatment sites included as covariates. Discrete variables are analyzed with Chi-Square or Fisher's Exact Tests. The primary objective of this study will be examined with survival analysis, both Kaplan Meyer Survival Analysis and log-rank test.
Repeated measurements analysis will be performed, where applicable, for analysis of the secondary objectives.

Quality control
There are 10 sites participate which are led by the Second Xiangya The Second Xiangya Hospital of the Central South University coordinates monitoring and data entry. A study start-up meeting is an efficient strategy to initially familiarized site staff with the protocol and provided study procedure training. The trial originator has provided instructional materials to all study sites and organizes an initial five-day training event that occurred prior to the implement of the trial. Reliability assessment of the major rating scales has been carried out. The originators of the intervention provide initial training in the procedure and monthly supervision of videotaped sessions.