Design

An open-label, randomized, follow-up clinical trial in a natural setting.

Time and setting

This study was performed at the outpatient clinic of the Second Xiangya Hospital of Central South University, China, from October 2008 to April 2010.

Subjects

One hundred outpatients were recruited. Schizophrenia or schizophreniform disorder was diagnosed by two qualified psychiatrists using the Structured Clinical Interview according to the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) criteria (American Psychiatric Association, 1994).

The following criteria were met for inclusion in the study: Han Chinese (chosen to maintain a homogeneous sample); aged 16 to 35 years; first-episode patients without previous exposure to any antipsychotic or other medication affecting cognitive function; course of illness lasting for at least 1 month but no longer than 2 years; PANSS^[32] total score higher than 60 at baseline; education over 9 years; agreeable to take part in a neurocognitive assessment and to sign the informed consent form.

Patients were excluded for the following reasons: history of brain injury; significant substance abuse; pregnancy or nursing; serious risk of suicide; severe, unstable medical illness; unwilling to take any research medication or accept cognitive testing; refusal to sign informed consent form.

All study procedures were performed in accordance with the Administrative Regulations on Medical Institution, issued by the State Council of China^[33]. All patients or their legally authorized representatives gave written informed consent for their participation after receiving a detailed description of the study procedures, including risks and benefits.

After obtaining written informed consent from the patients or their legally authorized representatives, and completing the baseline assessments, patients were randomly assigned to take olanzapine, risperidone or aripiprazole in a natural setting. Patients were given antipsychotic medication from low to high doses: olanzapine (2.5–20 mg per day), risperidone (1–4 mg per day), and aripiprazole (5–20 mg per day). In general, the initial dose of olanzapine was 2.5 mg per day, risperidone was 1 mg per day, and aripiprazole was   5 mg per day. After 2 days, the doses of the three medications were gradually increased until they reached the recommended maximum therapeutic dose. Researchers could flexibly adjust the medication dose according to the response of different patients. Anticholinergic medications (benzhexol hydrochloride, 2–4 mg per day) were used to relieve extrapyramidal side effects, and alprazolam could be prescribed to treat agitation and insomnia in the study-recommended dose ranges (0.4–0.8 mg per day). Patients should discontinue these medications within 24 hours prior to clinical or cognitive assessments.

Methods

Clinical measures of samples

Symptoms were assessed by PANSS^[32], which was also used to assess clinical efficacy.

The PANSS consists of 30 items rated on a seven-point scale (1 = absent, 7 = extreme). It has three subscales: positive (seven symptoms: P1–P7), negative (seven symptoms: N1–N7), and general psychopathology   (16 symptoms: G1–G16). The measurements included PANSS positive score (7–49), negative score (7–49) and total score (30–210). The higher the score, the more severe the symptoms.

Cognitive test battery of the samples

Patients underwent a battery of cognitive tests at baseline, and again following 6 months of treatment. The tests were performed in a fixed order on every patient and were conducted by the same rater trained in cognitive testing. The test battery, which comprised six tests, is described in detail as follows.

Hopkins Verbal Learning Test-Revised^[34]: This test assesses verbal memory and learning ability. The rater reads a list of 12 words to the subjects three times. After these readings, the subjects are asked to freely recall these words, and the rater records the number of correctly recalled words every time. After 25 minutes, the number of delayed recall words is also recorded. The total score of the three trials and delayed recall were used as outcome measures in this study. The total score is between 0 and 36; the score of delayed recall is between 0 and 12. Higher scores represent better performance.

Brief Visuospatial Memory Test-Revised^[35]: This test consists of six geometric figures that are printed in a    2 × 3 array on a page. The subject is shown the page for 10 seconds and then asked to draw the figures as accurately as possible in the correct location on the answer sheet. The score is assessed according to the criteria provided in the test manual. Each reproduction is given 2 points if both figure and location are correct. One point is given if either the figure or location is correct. The range of possible scores is 0–12 for each free recall trial. Total recall score over three learning trials was used as the outcome measure in the present study, giving a total recall score between 0 and 36. A higher score indicates better performance.

Spatial span subtest^[36]: Nonverbal working memory (forward and backward spatial span) is assessed in this test, using a three-dimensional board with 10 irregularly arranged numbered cubes. The test examiner taps a series of blocks at a rate of about 1 per second per block in a specific, predetermined pattern. Subjects must then tap the cubes in the same (or reverse) sequence. One point is awarded for each correct answer and the test is terminated after two incorrect consecutive trials. The score ranges from 0 to 16, whether forward tapping or reverse tapping. The total scores of forward and backward spatial span were used as outcome measures in the present study, resulting in scores for each subject ranging from 0 to 32, with a higher score indicating better performance.

Verbal Fluency Test (animal naming)^[37]: This psychological test requires subjects to say as many words as possible from a given category in 1 minute. The category can be phonemic or semantic. Animal naming is a semantic verbal fluency test. The total number of animals named in 1 minute, excluding repetitions and intrusive errors, was used as the outcome measure in this study, a higher score indicating better performance and reflecting both intact lexical storage and an ability to retrieve information from semantic memory. 

Stroop Color and Word Test^[38]: This test consists of three trials: stroop word, stroop color, and stroop color/word. First, the subjects read the name of the word (red, blue, or green) printed in black. Second, they name the color in which a word is printed. Finally, the names of colors are printed in colors that do not correspond to the words (e.g. “blue” printed in red), and subjects must read aloud the color, but not the word (i.e. “red” for this example). Every trial contains 100 items, and the subjects must read as quickly as possible for 45-second intervals. The number of correct names is recorded for every trial. Again, the higher the score, the better the performance in the test.

Digit symbol coding^[36]: This test consists of 133 digit- symbol pairs and requires the subjects to copy the corresponding symbol for a given number, as fast as possible. The number of correct symbols listed within 120 seconds was measured in the study. A higher score indicates a better performance.

Patients were required to complete the entire test battery in 30–40 minutes. Two different parallel versions of Hopkins Verbal Learning Test-Revised™ and of the Brief Visuospatial Memory Test-Revised™ were used to limit practice effects. These six tests include 10 variables and comprise five cognitive domains: verbal learning and memory (Hopkins Verbal Learning Test-Revised), visual learning (Brief Visuospatial Memory Test-Revised), processing speed (animal naming and digit symbol coding), working memory (spatial span subtest), and selective attention (Stroop test). 

For neurocognitive tests, all test measures were first converted to standardized z scores by setting the sample mean of each measure at baseline to 0 and the standard deviation to 1 for each test variable. The z scores were computed by using the baseline means and standard deviations from patients who completed that test at both baseline and follow-up. Because three domains (verbal learning, processing speed and selective attention) were examined using more than one test or variable, we used their summary scores, which were calculated by averaging the z scores for the contributing variables. A cognitive composite score was computed by averaging z scores of five cognitive domains for each treatment group.

Statistical analysis

Measurement data were expressed as mean ± SD. SPSS 15.0 software (SPSS, Chicago, IL, USA) was used to analyze the data. Continuous variables were checked to determine whether they satisfied normal distribution assumptions. All variables except for age and education fell within the normal distribution; the Kruskal-Wallis test was performed to compare these two variables. Categorical variables were analyzed using the chi-square test. One-way analysis of variance was used to analyze PANSS scores and cognitive variables of three treatment groups at baseline. A repeated measures analysis of variance was used to examine the clinical and cognitive effects of the three antipsychotics after 6 months of treatment, with the three independent treatment groups (olanzapine; risperidone; aripiprazole) used as between-subjects factors, and the two time points (baseline and 6 months) used as within-subjects factors. When a time or group-by-time interaction effect was significant on a particular domain, paired t-tests were used to examine within-group changes over time in a post-hoc analysis. Multiple comparisons were also performed using the Bonferroni test if there were significant differences in the between-group comparisons. The Pearson correlation was used to examine the relationship between treatment-related changes in an individual’s neurocognitive domain z scores and treatment-related change scores in the PANSS negative subscale. Effect sizes were determined using Cohen’s formula^[38-39]. All analyses used two-tailed levels of significance. Statistical significance was set at P < 0.05. When doing multiple comparisons, the Bonferroni adjustment P value was set at P < 0.017.

实验设计及文章构思特点：
以往的研究纳入的患者多为慢性精神分裂症患者、在服用研究药物之前以服用过其他抗精神病药物、并且合并多种其他药物、观察时间较多(6-12周)， 无法判断药物的真正疗效。而研究采用随机、开放性的研究，纳入的患者为未用过抗精神病药的首发精神分裂患者，具有同质性；采用的认知测验为患者易于耐受的测验；并进行了6个月随访研究；为便于对不同药物总的认知改善进行比较，对各个认知测验成绩进行了标准化的转化，可以观察到奥氮平、利培酮和阿立哌唑3种药物对患者认知的真正疗效。