Qigong-Based Therapy for Treating Adults with Major Depressive Disorder: A Meta-Analysis of Randomized Controlled Trials

This current meta-analysis review was conducted to examine the effectiveness of Qigong-based therapy on individuals with major depressive disorder. Six electronic databases (PubMed, PsycINFO, Cochrane Library, and Web of Science, Chinese National Knowledge Infrastructure, and Wangfang) were employed to retrieve potential articles that were randomized controlled trials. The synthesized effect sizes (Hedges’ g) were computerized to explore the effectiveness of Qigong-based therapy. Additionally, a moderator analysis was performed based on the control type. The pooled results indicated that Qigong-based therapy has a significant benefit on depression severity (Hedges’ g = −0.64, 95% CI −0.92 to −0.35, p < 0. 001, I2 = 41.73%). Specifically, Qigong led to significantly reduced depression as compared to the active control groups (Hedges’ g = −0.47, 95% CI −0.81 to −0.12, p = 0.01, I2 = 22.75%) and the passive control groups (Hedges’ g = −0.80, 95% CI −1.23 to −0.37, p < 0.01, I2 = 48.07%), respectively. For studies which reported categorical outcomes, Qigong intervention showed significantly improved treatment response rates (OR = 4.38, 95% CI 1.26 to 15.23, p = 0.02) and remission rates (OR = 8.52, 95% CI 1.91 to 37.98, p = 0.005) in comparison to the waitlist control group. Conclusions: Qigong-based exercises may be effective for alleviating depression symptoms in individuals with major depressive disorder. Future well-designed, randomized, controlled trials with large sample sizes are needed to confirm these findings.


Introduction
Clinical depression, also referred to as major depressive disorder (MDD), is a common debilitating mental disorder and is a leading cause of disability [1]. In fact, according to the statistics of the World Health Organization, there are more than 300 million individuals with MDD worldwide [2]. Patients with MDD often receive various forms of treatment (i.e., psychotherapy, pharmaceutics (antidepressants), or a combination of these two first-line therapies) [3]. Although these treatments have been shown to have therapeutic effects for those with MDD [4,5], they are subject to several limitations, such as high dropout rates (e.g., 12-40% during an 8-week psychotherapy), low remission rates, and numerous medication-related side effects (e.g., nausea, diarrhea, excessive sedation, and sleep problems) [6][7][8]. Considering the drawbacks of these first-line therapies, alternative and complementary therapies are needed to be developed to treat MDD [9]. Qigong is a traditional, self-healing, mind-body therapy that originated from traditional Chinese medicine (TCM), dating back to nearly four thousand years ago [10][11][12]. The term Qigong consists control group as a comparison, such as a waitlist, usual care, pharmacological therapy, or walking; and (6) reported either response rate, remission rate, and/or depression severity. The exclusion criteria were: (1) individuals diagnosed with other primary psychiatric disorders (e.g., major anxiety disorder) or mild cognitive impairment; (2) conference proceedings, case-studies, cross-sectional studies, controlled studies with no randomization or review; (3) non-Qigong interventions; and (4) duplicated publications.
Regarding study selection, removing both irrelevant and duplicate articles was conducted by an investigator screening the titles and abstracts. Two investigators then independently conducted full-text reviews to screen the remaining articles. All disagreements between the two investigators were resolved by seeking a third party's viewpoint.

Data Extraction
The following information was extracted to a data extraction table: Reference (first author and year of publication), participant characteristics (diagnostic criteria, percentage of MMD, study location, sample size, dropout rate, percentage of female participants, ethnicity, and mean age), intervention protocol (Qigong type, group or individual practice, qualification of instructor, intervention duration and follow-up period, training dosage, Qigong-related adverse events, and co-intervention), outcome measures, and study quality (allocation concealment, intention-to-treat analysis, and blinding of assessors) [37]. Quantitative data were extracted as well, including the sample size, mean and standard deviation (SD) of outcome measures at baseline and post-intervention in each group.

Study Quality Assessment
Three critical items (allocation concealment, intention-to-treat analysis, and blinding of assessors) were employed to assess the methodological quality of the selected studies based on the existing literature [38,39]. Since poor randomization methods can exaggerate estimated treatment effects [40], the implementation of allocation concealment is critical. The allocation concealment is adequate if the central randomization (site remote from study location) or opaque sequentially-numbered envelopes were clearly described. A study was identified as an intention-to-treat analysis if all of the initially assigned participants in each group were included in the final data analysis, regardless of missing data or dropout during/after the intervention. Blinding means that people who performed the outcome assessments did not possess information about group allocation of the study participants.

Quantitative Data Synthesis and Analysis
The Comprehensive Meta-Analysis Version 2 Software (BioStat, Englewood, NJ, USA) was employed to perform the data synthesis. The synthesized effect size (Hedges' g), which expresses the magnitude of Qigong effects on the severity of depressive symptoms, was calculated with a 95% confidence interval (CI). The magnitude of Hedges' g was then classified as being either a small, medium, or large effect (small effect = 0.2, medium effect = 0.5, large effect = 0.8), with a negative value indicating lower depression severity due to the beneficial effects of Qigong in comparison to the control groups. Odds ratios (OR) with 95% CIs were calculated for both response rates and remission rates. Since the measuring instruments across the selected studies were different, a random-effects model was adopted. Study heterogeneity was assessed using the value of I-squared and were divided into three levels (low = 25% or below; medium = 25% to 50%; large = 75% to 100%) [37].
There were two trials that included more than one control group [41,42]. To reduce the unit-of-analysis error, the shared Qigong group was separated into two controls for the two comparisons, while the means and SD of the Qigong group were unchanged. In addition, the Beck Depression Inventory (BDI) and the 17-item Hamilton Depression Rating Scale (HAM-D17) were used to measure the depression severity in two trials [41,42]. Given that the HAM-D17 is the clinician-administered depression assessment scale [43] and the most frequently used instrument in the present review, we only included the quantitative data measured by the HAM-D17 for meta-analysis. Furthermore, control type may be a potential moderator that also has an influence on the outcomes. Therefore, we performed two comparisons (Qigong vs. active control and Qigong vs. passive control) of the meta-analysis separately. Finally, the Egger's test was applied to evaluate the publication bias [44]. Figure 1 depicts the detailed process of study selection. A total of 609 records were initially identified, seven randomized controlled trials with nine-arm were included for synthesized analysis [41,42,[45][46][47][48][49]. As shown in Table 1, the seven trials were published between 2004 and 2017. Within the trials altogether, there were 382 patients with MDD in either the Qigong group (n = 175) or control group (n = 207). The holistic trials were distributed in the USA (n = 3), China (n = 2), United Kingdom (n = 1), and Germany (n = 1). The Qigong therapy lasted from 1 to 12 weeks, but only one study used a 12-week follow-up assessment [41]. A group-based training mode was the most frequently used method in the Qigong practice (antidepressant medications and/or psychotherapy allowed), without adverse events reported. Depression severity was measured by four difference scales (HAM-D17, HAM-D24, BDI, and the Epidemiological Studies Depression Scale). Response rate (categorized as >50% improvement on the HAM-D17 score) and remission rate (HAM-D17 scores ≤ 7) were reported in two trials [41,45]. Therefore, we performed two comparisons (Qigong vs. active control and Qigong vs. passive control) of the meta-analysis separately. Finally, the Egger's test was applied to evaluate the publication bias [44]. Figure 1 depicts the detailed process of study selection. A total of 609 records were initially identified, seven randomized controlled trials with nine-arm were included for synthesized analysis [41,42,[45][46][47][48][49]. As shown in Table 1, the seven trials were published between 2004 and 2017. Within the trials altogether, there were 382 patients with MDD in either the Qigong group (n = 175) or control group (n = 207). The holistic trials were distributed in the USA (n = 3), China (n = 2), United Kingdom (n = 1), and Germany (n = 1). The Qigong therapy lasted from 1 to 12 weeks, but only one study used a 12-week follow-up assessment [41]. A group-based training mode was the most frequently used method in the Qigong practice (antidepressant medications and/or psychotherapy allowed), without adverse events reported. Depression severity was measured by four difference scales (HAM-D17, HAM-D24, BDI, and the Epidemiological Studies Depression Scale). Response rate (categorized as >50% improvement on the HAM-D17 score) and remission rate (HAM-D17 scores ≤ 7) were reported in two trials [41,45].

Effects of Qigong on Response Rate, Remission Rate, and Depression Severity
There were only two trials reporting response rate and remission rate. Of the two trials, the study by Yeung et al. [45] included a Qigong group and a passive control group, while two control groups (active and passive conditions) were used in the other study [42]. An odds ratio was computed across these two studies and the results showed that the Qigong intervention showed significant improvement in treatment response rate (OR = 4.38, 95% CI 1.26 to 15.23, p = 0.02) and remission rate (OR = 8.52, 95% CI 1.91 to 37.98, p = 0.005) compared with the waitlist control group. There was no significant publication bias for the seven included studies with the nine treatment arms based on the results of Egger's test (β= −1.25, p = 0.51).

Discussion
This meta-analytic review was conducted to statistically synthesize the evidence of the effectiveness of Qigong-based therapy on MDD. The findings from our review suggest that the group of TCM mind-body exercise shows some clinical effect in the treatment of MDD as compared to active/passive controls.
In terms of response and remission rates, more than 50% improvement on the HAM-D17 scores and HAM-D17 scores ≤ 7 were identified as positive effect respectively [45]. Results from this metaanalysis indicated that Qigong-based intervention may be significantly beneficial to improve the response and remission rate for MDD compared with the control group (p < 0.05). These results were in line with previous clinical study [41], which agreed that the participants who received 60 min of Tai Chi twice a week for 12 weeks achieved some improvement in their depression than other therapies (i.e., psychoeducation). It is likely that Qigong-based intervention combining intentional bodily movements, rhythmic respiration and mind adjustment can regulate the body's stress and then reduce depression symptoms [9]. Therefore, depression severity was significantly alleviated in our metaanalytic study. In addition, according to the different Qigong types, movement Qigong had a significant improvement in alleviating the depression (p < 0.01), and there was a marginal significant improvement on depression through practicing static Qigong (p = 0.06). However, the moderate effect sizes of alleviated depression symptoms were tentative because of including a small number of eligible studies in this current review. Further studies were needed to examine the efficacy of either movement Qigong or static Qigong or both Qigong styles on treating MDD.
Although Qigong-based intervention has a potential impact on clinical and public health, the exact mechanisms of how Qigong works in reducing MDD are unknown, using Qigong as an important adjunct therapy for treatment of MDD was positively effective based on the findings from this study. A contemporary concept hypothesizes that Qigong practitioners are able to combine their awareness of spirit with body posture, breathing, and activity to elevate physiological proprioception. Furthermore, it can enhance homeostasis of the internal environment [50]. There are a lot of advantages of using Qigong exercises, compared to the current first-line treatments (drugs and cognitive behavioral therapy), as an alternative method for treating individuals with MDD. Qigong exercises are characterized as easy to learn, and have few side effects, and are popular in a number of people across all ages and physical condition. In particular, Qigong exercise is an additional option for older adults with medication side effects. However, there are some potential

Discussion
This meta-analytic review was conducted to statistically synthesize the evidence of the effectiveness of Qigong-based therapy on MDD. The findings from our review suggest that the group of TCM mind-body exercise shows some clinical effect in the treatment of MDD as compared to active/passive controls.
In terms of response and remission rates, more than 50% improvement on the HAM-D17 scores and HAM-D17 scores ≤ 7 were identified as positive effect respectively [45]. Results from this meta-analysis indicated that Qigong-based intervention may be significantly beneficial to improve the response and remission rate for MDD compared with the control group (p < 0.05). These results were in line with previous clinical study [41], which agreed that the participants who received 60 min of Tai Chi twice a week for 12 weeks achieved some improvement in their depression than other therapies (i.e., psychoeducation). It is likely that Qigong-based intervention combining intentional bodily movements, rhythmic respiration and mind adjustment can regulate the body's stress and then reduce depression symptoms [9]. Therefore, depression severity was significantly alleviated in our meta-analytic study. In addition, according to the different Qigong types, movement Qigong had a significant improvement in alleviating the depression (p < 0.01), and there was a marginal significant improvement on depression through practicing static Qigong (p = 0.06). However, the moderate effect sizes of alleviated depression symptoms were tentative because of including a small number of eligible studies in this current review. Further studies were needed to examine the efficacy of either movement Qigong or static Qigong or both Qigong styles on treating MDD.
Although Qigong-based intervention has a potential impact on clinical and public health, the exact mechanisms of how Qigong works in reducing MDD are unknown, using Qigong as an important adjunct therapy for treatment of MDD was positively effective based on the findings from this study. A contemporary concept hypothesizes that Qigong practitioners are able to combine their awareness of spirit with body posture, breathing, and activity to elevate physiological proprioception. Furthermore, it can enhance homeostasis of the internal environment [50]. There are a lot of advantages of using Qigong exercises, compared to the current first-line treatments (drugs and cognitive behavioral therapy), as an alternative method for treating individuals with MDD. Qigong exercises are characterized as easy to learn, and have few side effects, and are popular in a number of people across all ages and physical condition. In particular, Qigong exercise is an additional option for older adults with medication side effects. However, there are some potential disadvantages in actual life, such as a lack of qualified Qigong instructors in some places, non-standardized Qigong exercises, and non-adherence to long-term practices.
Several methodological limitations need to be noted. First, the subjective bias may exist in participants. Although eligible randomized controlled trials were included, participants still knew the allocation of the intervention (i.e., if they received Qigong training or not). Second, in most studies, participants were given mixed treatment, such as a combination of medication and Qigong. To some extent, it is difficult to determine if the Qigong alone, both Qigong and medication (synergetic intervention effect), or the usual treatment can contribute to alleviating their symptoms. However, significant effects of Qigong, as a complementary therapy, were observed to treat depressive disorder in this current study. Third, as large spans of time of Qigong practice were employed in the included studies, an optimal Qigong prescription was not easy to recommend for patients. It is possible that Qigong provides a number of benefits for human health based on practitioners daily self-practice, such as movement Qigong (45-60 min, 2-3 times/week) and static Qigong (50 min, once a day). Lastly, it is an interest point that, as both types of Qigong were effective through integrating a small number of studies, future studies may investigate whether the combination of movement Qigong and static Qigong are effective for MDD.

Conclusions
Our meta-analysis results suggest that Qigong may be an effective complementary intervention to treat individuals with MDD. Participants may practice movement Qigong for 45-60 min, two to three times weekly, for 12 weeks, and practice static Qigong for 50 min every day in a clinic. As there are some methodological limitations in the empirical studies included, carefully interpreting these findings is required. Meanwhile, to further investigate the efficacy of Qigong-based intervention on MDD, it is necessary to study the quality of randomized controlled trails with well-researched design.