East Asian Arch Psychiatry 2014;24:169-173

SPECIAL COMMUNICATION

中国首发精神分裂症临床试验（CNFEST）：背景和研究设计

韩雪、原岩波、于欣、赵靖平、王传跃、陆峥、杨甫德、邓红、武阳丰、GS Ungvari、项玉涛、赵凤琴

Dr Xue Han, MD, Peking University Sixth Hospital, Peking University Institute of Mental Health, Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing, China.
Dr Yan-Bo Yuan, MD, Peking University Sixth Hospital, Peking University Institute of Mental Health, Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing, China.
Dr Xin Yu, MD, Peking University Sixth Hospital, Peking University Institute of Mental Health, Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing, China.
Dr Jing-Ping Zhao, MD, Mental Health Institute, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
Dr Chuan-Yue Wang, Beijing Anding Hospital, Capital Medical University, Beijing, China.
Dr Zheng Lu, Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Dr Fu-De Yang, Center for Biological Psychiatry, Beijing Hui-Long-Guan Hospital, Beijing, China.
Dr Hong Deng, Mental Health Center, West China Hospital, Sichuan University, Chengdu, Sichuan province, China.
Mr Yang-Feng Wu, the George Institute for Global Health at Peking University Health Science Center, Beijing, China.
Dr Gabor S. Ungvari, The University of Notre Dame Australia / Marian Centre, Perth, Australia.
Dr Yu-Tao Xiang, Faculty of Health Sciences, University of Macau, Macao, China.
Dr Helen Fung-Kum Chiu, Department of Psychiatry, The Chinese University of Hong Kong, Hong Kong SAR, China.

Address for correspondence: Dr Xin Yu, Peking University Sixth Hospital, Peking University Institute of Mental Health, Key Laboratory of Mental Health, Ministry of Health (Peking University), Huayuanbeilu 51, 100191, Haidian District, Beijing, China.
Tel: (86-10) 82801999; Email: yuxin@bjmu.edu.cn

Submitted: 15 May 2014; Accepted: 12 August 2014

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Introduction

Schizophrenia is a complex illness with various clinical manifestations and prognoses. It is generally believed that the shorter the duration of untreated psychosis, the better the prognosis.^1,2 In order to improve the prognosis of schizophrenia, a number of studies^3-5 have focused on its early intervention.

In China, a considerable number of schizophrenia patients do not receive standardised and systematic treatment; in fact, approximately 70% of the estimated 4.8 million persons with schizophrenia in China do not receive regular treatment, possibly due to the failure of psychiatrists to comply with the treatment guidelines and patients’ poor treatment adherence.⁶ Despite the availability of treatment guidelines,^7,8 choosing the optimal antipsychotic medication for schizophrenia remains a major clinical challenge.^9-11 Most randomised controlled trials (RCTs) in schizophrenia are only short-term studies and include only highly selected patients,^12-16 therefore their findings are only partly relevant to clinical practice. Three recent large- scale drug trials^3,4,17 were conducted under ‘real-world’ conditions. The CATIE⁴ and CUtLASS¹⁷ studies involved only chronic patients despite the fact that many confounding factors are associated with chronicity of schizophrenia. Only the EUFEST study³ was carried out in first-episode schizophrenia (FES), but the findings of this multicentre European study probably cannot be applied directly to the Chinese sociocultural context and psychiatric settings. Lack of data about the optimal treatment of schizophrenia in China gave the impetus to design a ‘real-world’, open-label RCT entitled the Chinese First-Episode Schizophrenia Trial (CNFEST) to be conducted in Chinese clinical settings. This study aimed to compare the long-term effectiveness and tolerability of olanzapine, aripiprazole, and risperidone in Chinese FES patients, as well as to identify the socio- demographic and clinical factors associated with treatment adherence, cognitive impairment, social dysfunction, and prognosis at 1-year follow-up.

Methods

Settings

This multicentre, randomised, open-label clinical trial was conducted from 1 January 2008 to 31 December 2010. Six participating psychiatric centres located in North, West, East, and Central China were selected. These included Peking University Sixth Hospital (Beijing); Anding Hospital, Capital Medical University (Beijing); Huilongguan Hospital (Beijing); Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine (Shanghai); West China Hospital, Sichuan University (Chengdu, Sichuan); and Mental Health Institute, Second Xiangya Hospital, Central South University (Changsha, Hunan).

Study Criteria

The inclusion criteria were: (1) both in- and out-patients, (2) both genders, (3) diagnosis of schizophrenia established with Structured Clinical Interview for the DSM-IV Axis I Disorder, patient edition, (4) aged between 18 and 45 years, (5) onset at age ≥ 15 years, (6) first episode of schizophrenia, (7) no previous psychiatric treatment (‘drug-naïve’ status), and (8) ability to understand the contents of interview and provide written informed consent.

The exclusion criteria were: (1) a history or diagnosis of major medical conditions, (2) a history of alcohol and / or drug abuse or dependence, and (3) contra-indication to olanzapine, aripiprazole, or risperidone.

The study was conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice guidelines. The study protocol was approved by the medical ethics committees of the 6 participating hospitals.

Treatment

A total of 600 FES patients were consecutively recruited in the study. They were randomly assigned to 1 of 3 treatment groups, i.e. treatment with risperidone, aripiprazole, or olanzapine, by a computer-generated table, and then followed up for 1 year. During the follow-up period, if the treatment failed as judged by the investigators and / or the patient, the patients entered the next stage of the trial.

There were 3 stages of clinical intervention (Fig). In Stage 1, all 600 patients started antipsychotic monotherapy; antipsychotic doses were increased to a standard therapeutic range (3-6 mg risperidone, 15-30 mg aripiprazole, or 10-25 mg olanzapine per day) by the research psychiatrist in 2 weeks. Patients were assessed monthly by the research team for therapeutic effects and adverse events. During this stage, other antipsychotic medications were forbidden; if necessary, small doses of benzodiazepines (0.5-1.5 mg oral lorazepam or 2-4 mg oral or intramuscular clonazepam per day) could be prescribed for agitation and oral benzhexol (2-6 mg per day) or promethazine (25-75 mg per day) for extrapyramidal side-effects (EPS). At Stage 2, if no satisfactory effect was observed after at least 6 to 8 weeks but not more than 3 months (< 50% reduction on the total score of the Positive and Negative Symptom Scale [PANSS]) or intolerable adverse effects (severe EPS or weight gain > 10% of body weight) appeared, the research psychiatrist could change the antipsychotic to 1 of the other 2 study drugs while the monthly follow-ups continued. As in Stage 1, other antipsychotics were forbidden while the same adjunct medications could be administered. At Stage 3, pharmacotherapy could be switched to any other atypical antipsychotic including long-acting medications. Furthermore, a combination with other antipsychotics or a certain adjunctive antidepressant was allowed for patients who still could not reach satisfactory outcome after the previous 2 stages. Some patients were moved directly from Stage 1 to Stage 3 under special circumstances. For example, if the antipsychotic treatment was unsuccessful after 3 months (< 50% reduction on the PANSS score) or the weight gain exceeded 10% but the patient insisted on continuing the initial antipsychotic, then with the research psychiatrist’s consent, s/he could enter Stage 3. Also, if the antipsychotic drug used in Stage 1 had to be augmented with another antipsychotic or an adjunct antidepressant for > 2 weeks, patients had to skip Stage 2 and enter Stage 3. Patients who moved from Stage 1 to Stage 3 continued to be followed up for the rest of the 1 year.

Instrument and Evaluation

Basic socio-demographic and clinical data were collected with a form designed for the study. Duration of untreated psychosis was defined as the period between the onset of any obvious psychotic symptoms and the start of the antipsychotic treatment.

Mental state was assessed by trained psychiatrists at baseline and at 4, 8, and 13 weeks and then at 3-month intervals until the end of 1-year follow-up. An additional clinical assessment took place at the commencement of any medication change.

Symptom severity was evaluated with the PANSS^18,19 and Clinical Global Impressions Severity and Improvement scales.²⁰ Adverse events induced by antipsychotics were assessed using the Udvalg for Kliniske Undersøgelser side-effect scale.²¹ Treatment adherence was assessed with the 10-item version of Drug Attitude Inventory.^22-24 Social functions were assessed using the Personal and Social Performance scale.^25,26 Dropout was defined as discontinuation of treatment or withdrawing the consent to participate in the study.

Cognitive performance was evaluated at baseline, 6 months, and endpoint with a neuropsychological test battery comparable to the MATRICS Consensus Cognitive Battery (MCCB). The test battery included 5 tests of MCCB (Hopkins Verbal Learning Test–Revised [HVLT- R], Brief Visuospatial Memory Test–Revised [BVMT-R], Trail Making Test Part A, category fluency test, animal naming and Wechsler Memory Scale–spatial span subtest), and 8 alternative tests (Wechsler Adult Intelligence Scale digit symbol-coding subtest, symbol search subtest,²⁷ Word sound fluency test, Grooved Pegboard Test, Color Trails Test, Stroop Color-Word Test, Wisconsin Card Sorting Test [64-item version],^27-29 and paced auditory serial addition task) that assessed 5 cognitive domains: verbal learning and memory, visual learning and memory, speed of processing, motor skills, and executive function. Two alternative forms of HVLT-R and BVMT-R were used to control the potential learning effects at 6 months and endpoint.

There were 2 to 3 psychiatrists responsible for clinical assessment and another 2 to 3 psychiatrists for performing neuropsychological tests at each site. All interviewers attended a 1-week training workshop on use of the rating instruments prior to the study. Prior to the main study, a pilot study involving 20 schizophrenia patients was conducted. The inter-rater reliability of all instruments was satisfactory (intraclass correlation coefficients or kappa values > 0.75).

Laboratory Tests

Blood samples were collected at baseline, at the time points of medication changes, and at the endpoint. Blood samples were used to monitor adverse drug effects such as metabolic syndrome and liver or kidney dysfunction. Blood samples were stored and would be used to detect biomarkers at a later stage of the study.

Data Management

An online research database was established for real- time data transmission, monitoring, management, and task assignment. Data collected from each study site were entered into the central database and saved by data managers. Information recorded with the paper version of the data collection forms was double-entered and checked by a data entry company.

Conclusion

Results of this study are expected to be published in 2015. We believe that the findings will have important implications for developing a standardised treatment strategy for FES. The next stage of trial will be conducted to examine contributors to relapse of FES patients.

Declaration

This study was supported by National Key Project of Scientific and Technical Supporting Programs from the Ministry of Science and Technology of China (No. 2007BAI17B04). The Clinical trials.gov ID of the study is NCT01057849.

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