Abstract
Objective:
To examine the effects of Hatha yoga therapy on resilience, brain-derived neurotrophic factor (BDNF) levels, and salivary alpha amylase (SAA) activity in patients with schizophrenia-spectrum disorders.
Design and participants:
Single-blinded, randomized controlled study in which outpatients with schizophrenia or related psychotic disorders (according to International Classification of Diseases, 10th Revision) were randomly assigned to a yoga or a control group.
Setting:
November 2012–April 2013 at Yamanashi Prefectural Kita Hospital, Japan.
Interventions:
In the yoga group, patients received weekly 1-hour Hatha yoga sessions, in addition to regular treatment, for 8 weeks. Those in the control group underwent regular treatment, which included a daycare rehabilitation program.
Outcome measures:
Assessments included the 25-item Resilience Scale (RS), Positive and Negative Syndrome Scale (PANSS), plasma and salivary BDNF level, and SAA activity.
Results:
Fifty patients participated (25 in each group; mean age±standard deviation, 50.9±11.3 years; mean duration of illness, 25.0±10.3 years; mean total PANSS score, 78.2±17.3). No significant differences in changes in any variable from baseline to week 8 were found between the two groups (changes in the yoga group versus the control group: RS score, −1.6±19.9 versus 0.3±17.2; PANSS score, 0.5±12.0 versus 5.0±15.6; plasma BDNF, 41.6±377.0 pg/dl versus 73.4±346.0 pg/dl; SAA, −26.2±72.6 kU/l versus −13.8±68.0 kU/l, respectively).
Conclusions:
Adjunct yoga therapy showed no positive changes in resilience level or stress markers. Duration and intensity of yoga sessions and the focus on patients with chronic illness may explain the negative observations in light of past positive evidence regarding yoga therapy.
Y
“Resilience” is defined as a positive adaptation and maintenance of competent function even in the face of prolonged stress and adversities. 12,13 Some individuals, despite marked negative circumstances and risk factors, remain healthy or easily recover from adverse events, while others under similar conditions seem vulnerable to disorders. 14 Pathoetiology of schizophrenia has conventionally been investigated to seek new treatment approaches that will normalize the aberrant conditions. However, while such a traditional approach is valid, it is also critically important to focus on patients' resilience in order to understand mechanisms of recovery of this illness. In fact, good resilience increases the chance of long-term recovery in patients with schizophrenia. 15 Thus, the concept of resilience has recently gained wide attention. Because practicing yoga could reduce stress levels, it would be beneficial to test the idea that such therapy may have some beneficial effects on resilience levels in patients with schizophrenia. No existing studies appear to have studied this topic.
Stress suppresses neurogenesis through a process that involves brain-derived neurotrophic factor (BDNF). 16 Salivary alpha amylase activity (SAA) levels increasingly can be used as an accessible measure of sympathetic nervous system reactivity to stressors. 17 However, no data are available on yoga's effects on those measurable biological stress markers.
On the basis of this background, the current 8-week, single-site, single-blind, randomized controlled trial evaluated the effects of adjunctive weekly Hatha yoga therapy on resilience level, BDNF, and SAA activity in outpatients with schizophrenia-spectrum disorders.
Materials and Methods
Study design
In this study, eight weekly sessions of Hatha yoga therapy were added to ongoing regular psychopharmacologic treatment, together with a follow-up visit after an additional 8 weeks. This study was conducted in Yamanashi Prefectural Kita Hospital, Yamanashi, Japan, between November 2012 and April 2013. The hospital's institutional ethics board approved the study, and all participants provided written informed consent after being given a full description of the study. The study was registered at the University Medical Information Network Clinical Trial Registry (Identifier: UMIN000009305).
Participants
Outpatients who were diagnosed with schizophrenia or related psychotic disorders (F20–F25 according to the International Classification of Diseases, 10th edition), 18 were age 18 years or older, had been receiving the same medications for the 8 weeks preceding entry, and were registered in the daycare center in the hospital were approached and asked to participate in this study. Patients who were incapable of providing consent or suffered from active alcohol abuse or other psychiatric comorbidities were excluded; to ensure representativeness of the sample, no other exclusion criteria were applied. Medications were kept constant by the patients' treating psychiatrists throughout the study period unless a change was clinically indicated.
Intervention
The patients were randomly assigned to either a yoga therapy group or treated-as-usual group. The randomization was performed by using sealed envelopes prepared by physicians at Yamanashi Prefectural Kita Hospital who were not involved in this study. An envelope method was used to randomly divide the patients into two groups. A simple randomization list with no special stratification or blocks was made by using a computer program. One of the four physicians opened the envelopes after the baseline assessment.
Patients assigned to the yoga group received a weekly 1-hour session of Hatha yoga therapy between 9:40 and 10:40 a.m. on Mondays in the hospital gymnasium for a total of eight sessions. Participants were asked not to perform self-practice of yoga therapy at home. The sessions were provided as an adjunct to regular ambulatory treatment by one of the authors, who was an instructor with a master's degree in Hatha yoga. Each session consisted of gentle yoga stretches and simple movements in coordination with breathing (gentle movements of major muscle groups), asana (twisting poses and standing poses), deep relaxation, and breathing exercises. 19 After the completion of the 8-week intervention, patients received treatment as usual but did not receive any yoga therapy until the follow-up assessment was performed.
Patients in the control group attended a weekly regular daycare program (which provided social skills and walking) for 8 weeks. After the completion of the 8-week observation period, the patients in this group were allowed to attend Hatha yoga sessions upon request, which was offered outside the present trial.
Outcome measures
The primary outcome measure was resilience level at week 8 assessed with the 25-item Resilience Scale. 20 This scale measures the degree of individual resilience and is considered to represent a positive personality characteristic that enhances individual adaptation. The scale covers five factors of resilience: purpose, perseverance, self-reliance, equanimity, and existential aloneness. Items are scored on a 7-point scale ranging from 1=disagree to 7=agree, with possible scores ranging from 25 to 175; a higher score indicates greater individual resilience.
The secondary outcome measures included fasting blood glucose, total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, plasma and salivary BDNF, and SAA. These measurements took place between 9:00 a.m. and 12:00 p.m. at baseline and week 8 in both groups. The following assessments were also performed: the Positive and Negative Syndrome Scale (PANSS), 21 the Drug Induced Extrapyramidal Symptoms Scale (DIEPSS), 22 the Functional Assessment for Comprehensive Treatment of Schizophrenia (FACT-Sz), 23 and the EuroQol-5 dimensions (EQ-5D) classification system. 24 Follow-up assessments at week 16 in the yoga group included the RS, fasting blood glucose, total cholesterol chol, HDL cholesterol, LDL cholesterol, triglycerides, BDNF, SAA, and the EQ-5D.
All assessments were performed by trained psychiatrists who were blind to the patients' allocations and were not involved in the yoga therapy. Information collected included sex, age, duration of illness, body–mass index, physical comorbidities, waist circumference, and psychotropic medications. Daily doses of antipsychotics, including depot antipsychotics, were converted to chlorpromazine equivalents. 25,26
Venous blood samples were centrifuged at 3000 rpm for 10 minutes. All plasma samples were then stored at −30° until analyzed. Plasma and salivary concentrations of BDNF were measured according to the procedure supplied by the manufacturer (CYT306; Millipore Corp., Bedford, MA). To quantify SAA, a salivary alpha-amylase monitor (NIPRO®, Osaka, Japan) was used. This biosensor is composed of a disposable test strip and a hand-held reader. The precision (coefficient of variation) was reported as 8.1%, and its repeatability has measurement reliability. 27 The saliva sample was collected by dipping a sampling strip under the tongue for 30 seconds. The level of SAA was used as a proxy of acute stress. 17
Statistical analyses
No formal sample size calculation was performed because there has been no study on which to base sample size estimation. Statistical analyses were carried out using SPSS software, version 20 (IBM Corp., Armonk, NY). Patients' baseline characteristics were compared between the two groups by using the chi-square test or the independent t-test. The Mann-Whitney U test was used for age, duration of illness, body–mass index, dose of antipsychotics, FACT-Sz score, DIEPSS score, EQ-5D (index), SAA, triglycerides, HDL cholesterol, fasting blood glucose, and plasma and salivary BDNF because these were not distributed normally (according to the Shapiro-Wilk test of normality). Analysis of covariance (ANCOVA) with baseline values as covariates was used to compare changes at week 8 in the variables of interest between the yoga and control groups. In addition, repeated-measures analysis of variance was used to compare the variables between baseline and weeks 8 and 16 in the yoga group. When appropriate, post hoc analyses were performed with Bonferroni correction. The Pearson test was used to examine correlations in the changes of the variables. Main analyses were performed by using a last-observation-carried-forward method. Completer analysis was also used. All tests were two tailed, and p<0.05 was considered to represent a statistically significant difference.
Results
Patient characteristics
Eighty-one outpatients with schizophrenia-spectrum disorders registered in the daycare center were approached for possible participation in this study. Nineteen outpatients declined to participate because of their schedules and 12 had little interest in yoga therapy. Thus, 50 outpatients agreed to participate in this study and were allocated to either the yoga therapy group (n=25) or the control group (n=25). Characteristics and disposition of participants are shown in Table 1 and Figure 1, respectively; there were no significant differences at baseline between those two groups.

Flow of patients through the study.
Unless otherwise noted values are expressed as the mean±standard deviation. Group differences were compared by using chi-square test, independent t-test, or the Mann-Whitney test (see text for details).
BDNF, brain-derived neurotrophic factor; CPZE, chlorpromazine equivalent; DIEPSS, Drug Induced Extrapyramidal Symptoms Scale; EQ-5D, EuroQol 5 dimensions; FACT-Sz, Functional Assessment for Comprehensive Treatment of Schizophrenia; HDL, high-density lipoprotein; LDL, low-density lipoprotein; NA, not applicable; PANSS, Positive and Negative Syndrome Scale; SAA, salivary alpha-amylase activity; TG, triglyceride; VAS, visual analogue scale.
All participants were Japanese. Forty-one patients had schizophrenia and 9 had schizoaffective disorder. Physical comorbidities were as follows: hyperlipidemia (14%; n=7), hypertension (12%; n=6), diabetes mellitus (2%; n=1), hyperuricemia (2%; n=2), and arrhythmia (2%; n=2). Antipsychotic medications at baseline were olanzapine (32%; n=16), risperidone (20%; n=10), fluphenazine (14%; n=7), aripiprazole (10%; n=5), clozapine (8%; n=4), levomepromazine (4%; n=2), paliperidone (4%; n=2), bromperidol (2%; n=2), chlorpromazine (2%; n=2), haloperidol (2%; n=2), and sulpiride (2%; n=2). Twenty patients (40.0%) were receiving two or more antipsychotics. Medication adherence was acceptable judging from patients' interview for both groups. Only one participant (in the control group) experienced a change in the medication regimen from paliperidone, 3 mg/d, to risperidone, 4 mg/d, because of worsening delusions.
Treatment outcomes
Seven participants (28.0%) in each group prematurely withdrew from the study. The reasons of withdrawal were refusal to continue (6 participants in the yoga group and 5 participants in the control group), relapse (1 participant in the control group), and difficulty matching the schedule (1 each in the yoga and control groups).
No significant differences were observed in changes from baseline to week 8 in any of the variables of interest in both groups (Table 2). The ANCOVA with baseline values as covariates also showed no significant differences in changes in any of the variables of interest between the groups (Table 3). Additionally, no clinical gains were observed with this intervention, as indicated in Table 4.
Unless otherwise noted, values are expressed as the mean±standard deviation.
Unless otherwise noted, values are expressed as the mean±standard deviation. Group differences were compared by using the Mann-Whitney test.
Unless otherwise noted, values are expressed as the mean±standard deviation.
Significant difference (p<0.05).
In the yoga group, there was a modest correlation between the changes from the baseline to week 8 in the SAA activity and the RS (γ=0.403; p=0.046), but they were not significantly correlated in the control group (γ=0.203; p=0.158). As for the follow-up assessment at week 16 in the yoga group, only SAA significantly decreased compared with the baseline according to repeated-measures analysis of variance (Table 4); however, this difference was no longer seen after Bonferroni correction.
Completer analysis
Results of completer analysis are shown in the Supplementary Tables S1–S4 (Supplementary Data are available online at
Discussion
Main findings
To the authors' knowledge, this is the first study to assess the effect of Hatha yoga therapy on resilience, plasma and salivary BDNF, and SAA activity in patients with schizophrenia-spectrum disorders. Contrary to expectation, no variables significantly improved after the 8-week yoga intervention. However, these negative findings provide insights into improving the format and design of future yoga therapies, including frequency and duration, to achieve clinical gains in patients with schizophrenia discussed below. Such improvements might be beneficial given the past positive evidence of yoga therapy in improving physical and psychological conditions in other populations. 3 –6,28
Yoga therapy and resilience
Past evidence on yoga and resilience in healthy people and psychiatric patients is scarce and preliminary. Khalsa and colleagues reported that the resilience level, measured with the RS, slightly improved with yoga while most outcome measures, inclusive of the RS, exhibited a pattern of worsening in the control group over time among adolescents in secondary school. 29 Preventive benefits in psychosocial well-being were also reported when Kripalu yoga (which consists of three stages: willful practice, surrender, and meditation in motion) was practiced among students in 11th and 12th grades, although the RS scores did not significantly change. 30 On the other hand, women with mental distress significantly improved on measures of stress and psychological outcome after a 3-month yoga intervention. 31 Further, yoga therapy decreased SAA activity in both elderly and young people, 32 in whom a decrease in SAA is considered to represent an attenuated sympathetic tone. Relevant here is a finding that the SAA level was higher in patients with schizophrenia than in healthy people. 33
In the present study, the RS scores did not change in either group. The lack of significant changes may be attributable to characteristics of the sample, including their relatively older mean age compared with previous studies. Moreover, the mean duration of illness was as long as approximately 25 years, which represents the chronicity of the illness in the participants and may limit any room for improvements in resilience levels in the present study. SAA activity as an index of acute stress also did not change. However, this study assessed outpatients in the chronic stage of the illness, and any extrapolation of our findings to other patient populations, such as younger patients with acute disease or older patients, should be done with caution. Additionally, we did not evaluate more exhaustive parameters of stress and autonomic functioning, including hypothalamic-pituitary-adrenal axis hormones, heart rate variability, positional blood pressure, and baroreceptor sensitivity.
Yoga therapy and BDNF
BDNF is a trophic factor involved in the development of the brain and may influence neuroplasticity in schizophrenia. 34 Stress and depression suppress neurogenesis through a process that probably involves this substance. 16 Interventions that reportedly increase the BDNF level, such as exercise and antidepressant treatment, may help preserve brain function. In this context, practice of Sudarshan Kriya yoga increased serum levels of BDNF. 35 In a study on the effect of yoga on BDNF levels among depressed patients in India, Naveen et al. 36 observed that the change in BDNF did not significantly differ across three groups (i.e., yoga only, yoga and antidepressants, and antidepressants only). However, no studies have addressed this topic in patients with schizophrenia to date.
In the current study, levels of both plasma and salivary BDNF did not significantly change. The study did not control for dose or type of antipsychotics. In a review, Favalli et al. suggested that typical antipsychotics decrease serum BDNF levels while atypical counterparts maintain or increase the levels. 37 As such, use of various antipsychotics may have affected the current results. Additionally, a recent meta-regression showed the evidence of lowered levels of brain BDNF in patients with schizophrenia as they grow older; 34 the current participants were experiencing a relatively chronic course of their illness, with a mean illness duration of 25.0±10.3 years.
Recommendations for future studies
Several points should be considered in planning future studies. The first concerns duration and intensity of the yoga therapy. In a previous study, the authors focused on the effects of yoga on postural sway in patients with chronic schizophrenia. 19 Although the yoga intervention (i.e., a weekly 1-hour yoga session for 8 weeks) improved postural instability, it was insufficient to improve resilience and stress levels in this study. To further optimize yoga therapy, longer duration or greater intensity may be necessary in future trials. Second, intensity of yoga sessions should be considered; a once-a-week session may be insufficient. Third, the content of the yoga therapy may need to be adjusted for an elderly population to accommodate their physical strength and range of joint motion. Fourth, the data from multisite studies of yoga therapy in psychiatric patients are very scarce. Further yoga studies should deal with many participants from multiple institutions with diverse cultural/ethnic backgrounds. Finally, it is impossible to conduct double-blind studies with yoga, thereby necessitating more mechanistic research. 2
Limitations
Apart from the issues already discussed above, several other limitations should be noted. First, this study was limited by its small sample size (n=50) and lack of formal sample size calculation. This may have limited the statistical power to detect any possible differentials in resilience, BDNF, and SAA between the groups and thus makes the work preliminary. Second, the results should be interpreted in the context of type, duration, and intensity of the Hatha yoga intervention in this study. The yoga sequence involved different types of posture in this study. The effect of yoga therapy on psychological or pathological scales might be due to the modified yoga therapy used by one author. Finally, most participants in this study had long been taking various antipsychotics that potentially affect metabolic markers in a negative manner, which would make it difficult to capture any positive changes in a short study.
Conclusions
This appears to be the first study to focus on the effect of Hatha yoga therapy on resilience, BDNF, and SAA activity in patients with schizophrenia. The results were negative. However, these results alone should not discourage further critical appraisal of this intervention because of its theoretical benefits and past positive evidence in a variety of settings and populations. In light of the paucity of the available data, these results emphasize the need for further investigations on the potential benefits of yoga therapy in patients with schizophrenia.
Footnotes
Acknowledgments
We gratefully acknowledge the assistance of the regular day-care program staff in Yamanashi Prefectural Kita Hospital. The authors thank Drs. Ryoji Miyata, Akiko Kano, Fuminari Misawa, Mihoko Kobayashi, Hirokazu Shida, Waka Nogami, Hideaki Tani, Nobuhiro Nagai, Tatsuichiro Takahashi, Maho Hasebe, Toru Yamashita, Minako Sato, Hisashi Kida, Ryosuke Tarumi, Gentaro Miura, Saiko Ema, and Hodaka Yaegashi; Ms. Ai Otani; Ms. Aki Tozawa; and Ms. Atsuko Ikubo for their continuous support.
Author Disclosure Statement
Dr. Ikai has received manuscript fees or speaker's honoraria from Dainippon Sumitomo, Novartis, and Janssen Pharmaceutical within the past 3 years. Dr. Suzuki has received manuscript or speaker's fees from Astellas, Dainippon Sumitomo, Eli Lilly, Elsevier Japan, Janssen, Meiji Seika, Novartis, Otsuka, and Weily Japan. Dr. Uchida has received grants from Astellas Pharmaceutical, Eisai, Otsuka Pharmaceutical, GlaxoSmithKline, Shionogi, Dainippon-Sumitomo Pharma, Eli Lilly, Mochida Pharmaceutical, Meiji-Seika Pharma, Janssen Pharmaceutical, and Yoshitomi Yakuhin and speaker's honoraria from Otsuka Pharmaceutical, Eli Lilly, Shionogi, GlaxoSmithKline, Yoshitomi Yakuhin, Dainippon-Sumitomo Pharma, Meiji-Seika Pharma, Abbvie, and Janssen Pharmaceutical within the past 3 years. Dr. Fujii has received speaking fees from Janssen Pharmaceutical and Eli Lilly within the past 3 years. Dr. Mimura has received grants and/or speaker's honoraria from Asahi Kasei Pharma, Astellas Pharmaceutical, Daiichi Sankyo, Dainippon-Sumitomo Pharma, Eisai, Eli Lilly, GlaxoSmithKline, Janssen Pharmaceutical, Meiji-Seika Pharma, Mochida Pharmaceutical, MSD, Novartis Pharma, Otsuka Pharmaceutical, Pfizer, Shionogi, Takeda, Tanabe Mitsubishi Pharma, and Yoshitomi Yakuhin within the past 3 years.
References
Supplementary Material
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