Study Design: This study recruited hospitalized adult patients who had a relapse of schizophrenia. All participants had received antipsychotic treatment for a period of time previously. They have to meet the diagnostic criteria for schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). One hundred and twenty adult inpatients were recruited and were randomly assigned to receive olanzapine (n=60), risperidone (n=30) and paliperidone (n=30) in an allocation ratio of 2:1:1. The participants were allowed to change the dosage of antipsychotics and their hospitalization status according to the judgement of in-charged physicians during the study period.

The study was approved by the Institutional Review Board and written informed consents were obtained either directly from the patients or from their legal guardians after the study had been explained. The inclusion criteria for this study were: (1) age 18 to 65 years, (2) no major systemic illnesses based on physical examinations and laboratory test results, and (3) baseline PANSS total score≧60. The exclusion criteria were as follows: (1) participants not taking any antipsychotics in the previous one month, (2) participants were pregnant and lactating women, and (3) history of clozapine treatment in the previous 3 months, and (4) patients receiving long-acting antipsychotic injections in the preceding 6 months of enrollment.

This study was conducted by a 12-week, open-label and naturalistic randomized design. A tri-therapy (olanzapine, risperidone, and paliperidone) completely randomized design was adopted for this study, which involved three homogeneous groups of patients with a run-in period of 3 months. The patients were required to have discontinued all prior use of antipsychotics for a period of at least 7 days before their entry into the study. During wash-out period, administration of either oral benzodiazpines, hypnotics or injection of lorazepam to control anxiety, insomnia and aggression were allowed. After the wash-out period, the patients received treatment with an atypical antipsychotic drug, olanzapine, risperidone or paliperidone for 3 months.

The Positive and Negative Syndrome Scale (PANSS) rating scale was used to evaluate the changes of psychiatric symptoms in each time point. The subject patients were interviewed for the PANSS by senior psychiatrists. The raters in the present study had worked mainly on inpatient treatment of severe schizophrenic patients, and were well acquainted with symptoms of schizophrenia. Prior to the present study, all participating psychiatrists had received adequate training through the manual and they had had clinical experience in the PANSS rating before the study. At each time point if the scores of PANSS showed the patient's symptoms had worsened, the dosage would be adjusted based on the clinical judgment of in-charged senior psychiatrist. However, if the scores of PANSS were improved, the dosage was maintained. The recommended dose for the three groups were as follows: 10 to 20 mg daily for olanzapine, 4 to 6 mg daily for risperidone, and 6 to 12 mg daily for paliperidone. Throughout the study period, the paticipants were allowed to continuously use some concomitant medication, including lorazepam (up to 6 mg/day) for insomnia or agitation and biperiden (up to 6 mg/day) for treatment of extrapyramidal side effects. No other psychotropic agents were administered during the 12-week study.