Aripiprazole in the treatment of acute episode of schizophrenia: a real-world study in China

To the Editor: Schizophrenia is a progressive, debilitating disease.[1] Safe and effective treatment performed during the acute phase is the first step to improve prognosis, and it is critically important. Aripiprazole is known as a dopamine system stabilizer, and it exerts partial agonism with high affinity at dopamine D2 and serotonin (1A) (5-HT1A) receptors as well as antagonism at serotonin (5-HT2A) receptors.[2] It has been shown to be efficacious in amelioration of both positive and negative symptoms of acute schizophrenia, and it shows better tolerance than most antipsychotics.[3] We conducted a real-world study to further confirm the efficacy and safety of aripiprazole in patients with acute episodes of schizophrenia in China and tried to explore the clinical variables, including various drug regimens, that may be correlated with the efficacy of aripiprazole, and provide a basis for the optimization of aripiprazole treatment for patients with acute schizophrenia. This study was a single-arm, open-label, eight-week study and was conducted in 14 psychiatric hospitals [Supplementary file, https://links.lww.com/CM9/B397]. Inpatients aged 18 to 65 years with a diagnosis of schizophrenia defined by the International Classification of Diseases, 10th Revision were included. The criteria for included patients were: (1) total Positive and Negative Syndrome Scale (PANSS) scores were ≥70 at baseline; (2) the individual item scored ≥4 for at least two of the following PANSS items: P1, P2, P3, and P6; and (3) the PANSS-positive score was higher than the PANSS-negative score. The key exclusion criteria included: (1) concomitant unstable medical conditions or other mental diseases; (2) any evidence of suicide risk or history of violence; (3) previous allergic reaction to aripiprazole; (4) any history of neuroleptic malignant syndrome or serious extrapyramidal syndrome; and (5) women who were pregnant, planning a pregnancy, or breastfeeding. Besides, patients with treatment-resistant schizophrenia who had undergone electroconvulsive therapy within the past two months and those who had been enrolled in any other clinical trials within four weeks before enrollment of the study were also excluded. The study protocol was approved by the Ethics Committees of the Peking University Institute of Mental Health (No. 2017-24). All subjects signed the written informed consent before screening. The study has been registered on ClinicalTrials.gov (No. NCT03289026). Eligible patients received orally disintegrating aripiprazole tablets (Brisking,[4] Chengdu Kanghong Pharmaceutical Group Co., Ltd., Chengdu, Sichuan, China) for eight weeks. Doses were flexibly titrated to between 10 and 30 mg once daily. Other antipsychotics, anti-depressants, and mood stabilizers were prohibited. Benzodiazepines, anti-cholinergics, and β-receptor blockers were permitted when clinical indications existed, but the duration of continuous use of benzodiazepines did not exceed seven days. The primary endpoint was mean change from baseline to week 8 in the PANSS total score. The secondary endpoints included the rate of reduction in the PANSS total score, and the scores change of Clinical Global Impression-Improvement (CGI-I) and Clinical Global Impression-Severity of Illness (CGI-S), from baseline to endpoint. Assessments were performed at baseline, and weeks 2, 4, and 8 after initiation of treatment. The response rate (defined as the rate of reduction from baseline in the PANSS total score>30%) was also evaluated. Adverse events (AEs) were recorded during interviews and the Udvalg for Kliniske Undersogelser (UKU) Side Effects Rating Scale was used to evaluate the side effects induced by aripiprazole. Physical examination and clinical laboratory tests were carried out at the initial screening, four weeks after the initiation of treatment, and the end of the eight-week treatment regimen. Effectiveness analyses were performed on the full analysis set (FAS). Besides, the safety was also described based on the safety set (SS). SAS 9.4 software (version 9.4, Cary, NC, USA) was used for statistical analysis. Categorical variables were expressed as number (percentages); continuous variables were expressed as least-square means (LSMs) and 95% confidence interval (CI) or median (P25, P75). The mixed model for repeated measures analyses was used to compare the changes from baseline to endpoint in PANSS total score, PANSS score reduction rates, and CGI-S. The missing values were not filled. The total population was divided into the treatment-effective (TE) group and the treatment-ineffective (TIE) group according to whether the PANSS total score reduction rate was >30%. The baseline clinical demographic characteristics and medication administration information of the two groups were compared using the Fisher's exact test, Wilcoxon rank sum test, or chi-squared test, as appropriate. The variables with P < 0.2 in single factor analysis were included in multivariate logistic regression analysis. The odd ratio (OR) and its 95% CI were calculated to identify the factors influencing symptom improvement. A two-tailed P < 0.05 was considered statistically significant. This work covered 803 participants and enrolled 703 who met the inclusion criteria; and 543 completed the whole research process, eventually. FAS included 640 (91.0%) subjects, and SS included 703 (100.0%). Some indicators were not recorded in all the participants during the follow-up, resulting in only 616, 584, and 543 records on PANSS at week two, four, and eight, respectively, and 610, 578, and 540 on CGI-I and CGI-S. In total, 82.3% (527/640) of patients received a dosage of 30 mg/day, and the titration was relatively fast with a mean time to target dose of 8.4 (standard deviation = 4.87) days. In the FAS, the LSM change of PANSS total score was −30.63 (95% CI: −31.83, −29.42) at the second week, −43.73 (95% CI: −44.95, −42.51) at the fourth week, and −53.52 (95% CI: −54.76, −52.27) at the end of the eighth week. The means of PANSS score reduction rates were 30.0%, 43.5%, and 53.5% at the end of the second, fourth, and eighth weeks, respectively. The response rate was 50.5% (311/616) for aripiprazole at the second week, and it rose to 84.4% (493/584) and 96.3% (523/543) at the fourth and eighth weeks, respectively. The LSM changes in CGI-S score from baseline were −1.53 (95% CI: −1.61, −1.45), −2.29 (95% CI: −2.37, −2.21), and −3.13 (95% CI: −3.21, −3.05) at the end of second, fourth, and eighth weeks, respectively. According to the CGI-I score, 48.7% (297/610) of patients had improved at the end of the second week, and 76.8% (444/578) and 90.0% (486/540) had improved by the end of the fourth and eighth weeks, respectively. The baseline demographic and clinical characteristics of patients, who completed the whole study process, were divided into TE and TIE groups, are shown in Supplementary Table 1, https://links.lww.com/CM9/B397. TE group had a significantly lower proportion of higher BMI, a higher proportion of patients with shorter duration of illness, higher baseline PANSS total scores, baseline PANSS positive scores, PANSS excitatory factors scores, PANSS anxiety and depression factors scores, and a higher cumulative drug exposure than the TIE group. Compared with TIE group, patients in TE group were more likely to experience the first episode of schizophrenia and to be previously untreated. In multivariate logistic regression analyses, we found that patients with higher baseline excitatory factors (OR = 1.37, 95% CI: 1.08–1.75, P = 0.009), greater cumulative drug exposure (OR = 1.00, 95% CI: 1.00–1.01, P = 0.015) and being previously untreated (OR = 25.97, 95% CI: 3.78–178.30; P < 0.001) were more likely to be effectively treated by aripiprazole. A total of 390 (55.5%) patients reported at least one AE associated with aripiprazole, the most common of which was akathisia (29.2% [205/703]). Four participants discontinued treatment due to AEs, but there were no reports of serious AEs. According to the UKU, the other AEs with an incidence of ≥10% included tremors, tension or inner unrest, and reduced sleep duration. Almost all of these AEs were mild to moderate. At 8 weeks, the mean change from baseline in body weight was +0.7 kg. 5.6% of patients had weight gain ≥7% of the body weight at baseline. The proportions of patients with abnormal metabolic indicators including fasting blood glucose, high-density lipoprotein cholesterol and low-density lipoprotein cholesterol were decreased from baseline, but proportion of patients with abnormal the triglyceride increased slightly [Figure 1A]. At the endpoint, the proportion of patients with normal prolactin level increased (8 weeks vs. baseline: 96.9% vs. 87.8%) and the proportion of patients with moderate and severe hyperprolactinemia reduced [Figure 1B].Figure 1: Changes in proportion of patients with abnormal metabolic indicators and hyperprolactinemia from baseline to the end of eight weeks. (A) The change in the proportion of patients with abnormal blood glucose and blood lipids. Fasting blood glucose ≥6.1 mmol/L was abnormal; triglyceride ≥1.7 mmol/L was abnormal; cholesterol ≥5.2 mmol/L was abnormal; high-density lipoprotein <1.0 mmol was abnormal; low-density lipoprotein ≥4.1 mmol/L was abnormal. (B) The change in the proportion of patients with different severity of hyperprolactinemia. Mild, moderate and sever hyperprolactinemia were defined as the level of prolactin ≥530 mIU/L and <1060, ≥1060 mIU/L and <2120, and ≥ 2120 mIU/L, respectively.In this large-sample, real-world study, aripiprazole showed satisfactory efficacy in acute episodes of schizophrenia. In the present study, high dose and fast titration strategy was taken in the most of included patients, which differs considerably from the recommendations on the drug's label. This dosing strategy may be due to the consideration that aripiprazole is a partial agonist of dopamine D2 receptors, which may require a higher dose to achieve sufficient D2 occupancy and to achieve a reduction in DA neurotransmission pronounced enough to alleviate positive symptoms and to do so earlier.[5] Logistic regression analyses indicated that in addition to being previously untreated and having higher baseline excitatory factor scores, higher cumulative drug exposure may be correlated with a better efficacy of aripiprazole. In the present study, aripiprazole showed satisfactory safety despite with a high dose and fast titration dose stratge, but the AE of akathisia needs to be paid attention to. Aripiprazole may have some positive effects on metabolic disorders, which has raised concern with other second-generation antipsychotics, but these fingings need research and validation. This study has some limitations. First, as it was a real-world study, there was no strict control of grouping and a significant difference in sample size existed between two groups. Second, some variables associated with efficacy may not have been included in this study, so the analysis of relevant factors is only preliminary, and better controlled research must be performed to verify the findings of the present study. Third, the participants were exclusively adult inpatients with schizophrenia and so the results should not be generalized to whole populations. In summary, patients receiving antipsychotics for the first time with higher baseline excitatory factor scores and higher accumulative drug exposure are more likely to respond to aripiprazole. Aripiprazole has relatively satisfactory safety, but the AE of akathisia needs to be paid attention to. Acknowledgements The authors would like to thank Medieco Group Co., Ltd. (Beijing), who provided help in generating the data statistics used in the present study, and all the clinicians who helped to organize the study in each site. Funding The current work was partially supported by a grant from the Capital Medical Development Research Fund (No. 2020-2-4113). Conflicts of interest None.