Design
We conducted a single-blind, superior, randomized controlled trial (RCT) comparing conventional therapy combined with SBQE and conventional therapy for patients with schizophrenia. Once the recruitment process was completed, all eligible patients were randomized 1:1 to either the SBQE or the control group. The trial protocol has been published elsewhere [20].
The trial was registered at ClinicalTrials.gov (identifier: NCT05310955, on 22/02/2022) and (identifier: ChiCTR2200057373, on 10/03/2022). The study was approved by the Internal Review Board (IRB) of Shanghai Mental Health Center and was conducted following the Helsinki Declaration of 1975.
The recruitment process included a detailed introduction of the study by the study leader to the researchers responsible for recruitment. Subsequently, the researchers recruited participants in the rehabilitation ward. Upon registration, the recruiters conducted a comprehensive evaluation of the participants. Recruiters also provided detailed information regarding the study’s purpose, content, and potential benefits or risks to participants who met the research criteria. Finally, participants who agreed to participate in the study signed an informed consent form.
Participants
Patients diagnosed with schizophrenia were recruited from four rehabilitation wards at the Shanghai Mental Health Center from August 2022 to December 2022. Recruiters used the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 to confirm the diagnosis of schizophrenia and determine if the patients met the inclusion criteria.
The study’s inclusion criteria were as follows: (1) Han Chinese ethnicity; (2) aged ≥ 18 years; (3) had an education level ≥ 6 years; (4) met the diagnostic criteria for schizophrenia based on DSM-5; (5) were stable patients with schizophrenia living in a rehabilitation ward without relapse for the past 6 months; (6) exhibited residual negative symptoms, with at least one item ≥ 2 on the negative subscale of the Positive and Negative Syndrome Scale (PANSS) (N1-N7) [21]; (7) were taking second-generation antipsychotics; (8) had no history of Qigong training; (9) not participated in any other researches in the past 6 months.
The exclusion criteria were as follows: (1) were suffering from severe physical illnesses such as cardiovascular, lung, liver, kidney, and hematopoietic diseases; (2) were having severe cognitive impairment and/or mental retardation; (3) received electroconvulsive or rTMS therapy in past three months; (4) were having vision and/or hearing problems. The Mini-Mental State Examination (MMSE) was used for assessment, and patients with an MMSE score < 24 were identified as having severe cognitive impairment [22, 23].
Randomization and masking
Participants in this study were divided into SBQE and control groups in a 1:1 ratio using a random number table generated by SPSS V.24.0. An independent research coordinator placed the random numbers in opaque envelopes, which were labeled with the participant’s name and date of birth to ensure allocation concealment and prevent subversion of the allocation sequence. Before receiving the intervention, the therapist responsible for the intervention opened the envelope. In this study, evaluators and data analysts were blinded and only knew the number of participants but not their other information or grouping status. The therapists in charge of the intervention were not blinded, but they did not have contact with the evaluators and data analysts. Participants could not be blinded to their group assignment but were asked not to reveal their treatment status to the evaluators during the assessment. To prevent bias, an independent research coordinator directly contacted the patients instead of being approached by the researchers.
Interventions
Conventional therapy
Patients in the control group maintained their conventional therapy for 12 weeks. This therapy involved the use of psychiatric medication treatment and a routine rehabilitation program.
The routine rehabilitation program lasted 12 weeks and took place once a day for 1.5 h from Monday to Friday. It included activities such as general health education, reading, painting, annual work, gardening, and training in daily life skills. Therapists in the rehabilitation department conducted the program and kept records of the patients’ participation.
SBQE
Patients in the SBQE group received 12-week SBQE while maintaining the same routine rehabilitation program as the control group. A professional traditional Chinese exercise teacher instructed them for one week before the formal intervention began. The SBQE sessions occurred daily for 30 min, from Monday to Friday, for 12 weeks, totaling 60 workshops. The participants gathered in a quiet, spacious rehabilitation hall, and the researchers supervised the entire exercise. The exercise intensity was monitored using the Borg CR10 scale, targeting a level of 4–6, where the participant should feel somewhat severe but not very severe fatigue. If a participant’s Borg self-rated score was less than 4 or greater than 6, they were instructed to adjust their range of motion, speed, and breathing to increase or decrease exercise intensity. Exercise recording cards were used to monitor participants’ compliance in the SBQE group, and two research assistants recorded each exercise session. The intervention was considered valid if the participant’s actual exercise times accounted for more than 85% of the estimated exercise times.
We selected 6 sets of Qigong movements that can improve cognitive function from 4 TCM Qigong (Liuzijue, Baduanjin, Wuqinxi, and Yijinjing) and reorganized them into an SBQE for treating schizophrenia patients. As shown in Fig. 1, SBQE consists of the following eight actions: starting posture, ‘HE exercises’ in Liuzijue, ‘raising a single arm to regulate the spleen and stomach’, ‘looking back to treat five strains and seven impairments’, ‘shaking head and buttocks to expel heart-fire’ in Baduanjin, ‘plucking fruit like a monkey’ in Wuqinxi, ‘Wei Tuo presenting the pestle’ in Yijinjing and ending posture.
SBQE for treating schizophrenia patients
The 30-min SBQE includes (1) a 3-min warm-up period including joint activities such as head movement, chest expansion, arm vibration, body rotation, wrist and ankle movement and leg pressing followed by calm breathing and mental focusing; (2) a 20-min SBQE exercise period and (3) a 7-min cool-down period with the main content of muscle stretching and relaxation, including leg stretching, upper-back stretching, waist stretching, neck stretching and shoulder stretching while paying attention to breathe adjustment and mind relaxation.
Outcome measures
The primary outcome measure was the Chinese version of the Scale for the Assessment of Negative Symptoms (SANS) [24]. The SANS, the first diagnostic scale directly referring to deficit symptoms, was used to assess negative symptoms [25, 26]. It consists of five subscales: affective flattening, alogia, avolition-apathy, anhedonia-asociality, and attention. A higher SANS score indicates more severe negative symptoms. The assessment was carried out by blinded assessors at baseline and at the 12-week mark, which was the primary endpoint.
The secondary outcome measure was the Chinese version of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) [27, 28]. The Chinese version of RBANS has good reliability and validity in the application of schizophrenia patients. It can be used as a tool for the cognitive function level of schizophrenia patients [28]. It includes five dimensions: immediate memory, visuospatial/construction, language, attention, and delayed memory. Higher RBANS scores indicate better cognitive function. Similar to the SANS assessment, the RBANS assessment was conducted by blinded assessors at baseline and the 12-week mark, the primary endpoint.
All blinded assessors received training in the assessments of SANS and RBANS prior to the commencement of the study. The inter-rater correlation coefficients exceeded 0.8.
Sample size calculation
This study was a superiority trial. We used the calculation formula to determine the sample size for the superiority test based on the previous Scale for the Assessment of Negative Symptoms (SANS) scores (10.02 ± 1.66; 7.20 ± 0.11) found in related literature [29]. By setting alpha = 0.05, power = 90%, and superiority margin = 1, we obtained the minimum sample size of 15 for each group. We selected a superiority margin of 1 as it was deemed the minimum acceptable level for improving clinical experience. Assuming a 20% dropout rate and considering clinical operability, we enrolled 18 participants in each group.
Statistical analysis
The study adhered to the intention-to-treat principle (ITT) to analyze outcome data from all enrolled patients, including those who dropped out. Missing data for primary and secondary outcomes at 12 weeks were imputed using multiple imputations through predictive mean matching.
The Kolmogorov-Smirnov one-sample test was used to assess the distribution of the data. The chi-square test was used for categorical variables. The Mann-Whitney U-test was used to measure the continuity of non-normal variables. The t-test was used to assess the continuity of normal variables.
Mixed-effects regression analyses for repeated measures with maximum likelihood estimation were used with the assumption that data were missing at random. For the primary and secondary outcomes, the model included fixed effects of time, group, and an interaction effect of group×time, as well as a random intercept to account for individual differences. The interaction effect of group×time was used to evaluate group differences at week 12 (primary endpoint). In the post hoc test, the differences between the two groups at baseline (W0) and after treatment (W12) were reported. All statistical analyses were conducted using R Statistical software version 4.3.1 and SPSS 24.0. The 2-sided α value was set at 0.05. It was noted that due to the heightened risk of type I error resulting from multiple comparisons of outcomes, the findings should be considered exploratory.
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