For this RCT critical appraisal assignment, you will complete an appraisal of the following article=:? Here is a link to the article: ? ?A randomized

CASP Randomised Controlled Trial Standard Checklist: 11 questions to help you make sense of a randomised controlled trial (RCT)

Main issues for consideration: Several aspects need to be considered when appraising a randomised controlled trial:

Is the basic study design valid for a randomised controlled trial? (Section A)

Was the study methodologically sound? (Section B) What are the results? (Section C) Will the results help locally? (Section D)

The 11 questions in the checklist are designed to help you think about these aspects systematically.

How to use this appraisal tool: The first three questions (Section A) are screening questions about the validity of the basic study design and can be answered quickly. If, in light of your responses to Section A, you think the study design is valid, continue to Section B to assess whether the study was methodologically sound and if it is worth continuing with the appraisal by answering the remaining questions in Sections C and D.

Record ‘Yes’, ‘No’ or ‘Can’t tell’ in response to the questions. Prompts below all but one of the questions highlight the issues it is important to consider. Record the reasons for your answers in the space provided. As CASP checklists were designed to be used as educational/teaching tools in a workshop setting, we do not recommend using a scoring system.

About CASP Checklists: The CASP RCT checklist was originally based on JAMA Users’ guides to the medical literature 1994 (adapted from Guyatt GH, Sackett DL and Cook DJ), and piloted with healthcare practitioners. This version has been updated taking into account the CONSORT 2010 guideline (http://www.consort-statement.org/consort-2010, accessed 16 September 2020).

Citation: CASP recommends using the Harvard style, i.e. Critical Appraisal Skills Programme (2020). CASP (insert name of checklist i.e. Randomised Controlled Trial) Checklist. [online] Available at: insert URL. Accessed: insert date accessed.

©CASP this work is licensed under the Creative Commons Attribution – Non-Commercial- Share A like. To view a copy of this licence, visit https://creativecommons.org/licenses/by-sa/4.0/

Critical Appraisal Skills Programme (CASP) part of OAP Ltd www.casp-uk.net

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Study and citation: …………………………………………………………………………………………………………

Section A: Is the basic study design valid for a randomised controlled trial?

1. Did the study address a clearly focused research question? CONSIDER: Was the study designed to assess the outcomes of an intervention? Is the research question ‘focused’ in terms of: • Population studied • Intervention given • Comparator chosen • Outcomes measured?

Yes No Can’t tell o o

2. Was the assignment of participants to interventions randomised? CONSIDER: • How was randomisation carried out? Was

the method appropriate? • Was randomisation sufficient to eliminate

systematic bias? • Was the allocation sequence concealed

from investigators and participants?

Yes No Can’t tell o o o

3. Were all participants who entered the study accounted for at its conclusion? CONSIDER: • Were losses to follow-up and exclusions

after randomisation accounted for? • Were participants analysed in the study

groups to which they were randomised (intention-to-treat analysis)?

• Was the study stopped early? If so, what was the reason?

Yes No Can’t tell o o o

Section B: Was the study methodologically sound?

4. • Were the participants ‘blind’ to

intervention they were given? • Were the investigators ‘blind’ to the

intervention they were giving to participants?

• Were the people assessing/analysing outcome/s ‘blinded’?

Yes No Can’t tell

o o o o o

o o o

5. Were the study groups similar at the start of the randomised controlled trial? CONSIDER: • Were the baseline characteristics of each

study group (e.g. age, sex, socio-economic group) clearly set out?

• Were there any differences between the study groups that could affect the outcome/s?

Yes No Can’t tell o o o

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6. Apart from the experimental intervention, did each study group receive the same level of care (that is, were they treated equally)?

CONSIDER: • Was there a clearly defined study protocol? • If any additional interventions were given

(e.g. tests or treatments), were they similar between the study groups?

• Were the follow-up intervals the same for each study group?

Yes No Can’t tell o o o

Section C: What are the results?

7. Were the effects of intervention reported

comprehensively?

CONSIDER:

• • What outcomes were measured, and were

they clearly specified? • How were the results expressed? For

binary outcomes, were relative and absolute effects reported?

• Were the results reported for each outcome in each study group at each follow-up interval?

• Was there any missing or incomplete data? • Was there differential drop-out between the

study groups that could affect the results? • Were potential sources of bias identified? • Which statistical tests were used? • Were p values reported?

Yes No Can’t tell o o o

8. Was the precision of the estimate of the intervention or treatment effect reported?

CONSIDER: • Were confidence intervals (CIs) reported?

Yes No Can’t tell o o o

9. Do the benefits of the experimental intervention outweigh the harms and costs?

CONSIDER: • What was the size of the intervention or

treatment effect? • Were harms or unintended effects

reported for each study group? • Was a cost-effectiveness analysis

undertaken? (Cost-effectiveness analysis allows a comparison to be made between different interventions used in the care of the same condition or problem.)

Yes No Can’t tell o o o

Was a power calculation undertaken?

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Section D: Will the results help locally?

10. Can the results be applied to your local population/in your context?

CONSIDER: • Are the study participants similar to the

people in your care? • Would any differences between your

population and the study participants alter the outcomes reported in the study?

• Are the outcomes important to your population?

• Are there any outcomes you would have wanted information on that have not been studied or reported?

• Are there any limitations of the study that would affect your decision?

Yes No Can’t tell o o o

11. Would the experimental intervention provide greater value to the people in your care than any of the existing interventions?

CONSIDER: • What resources are needed to introduce

this intervention taking into account time, finances, and skills development or training needs?

• Are you able to disinvest resources in one or more existing interventions in order to be able to re-invest in the new intervention?

Yes No Can’t tell o o o

APPRAISAL SUMMARY: Record key points from your critical appraisal in this box. What is your conclusion about the paper? Would you use it to change your practice or to recommend changes to care/interventions used by your organisation? Could you judiciously implement this intervention without delay?

1. Study and citation:
2. Section D Will the results help locally:
3. Check Box2: Off
4. Q:
1. 1 consideration answers:
2. 2 consideration answers:
3. 3 consideration answers:
4. 5 consideration answers:
5. 6 consideration answers:
6. 7 consideration answers:
7. 8 consideration answers:
8. 9 consideration answers:
9. 10 consideration answers:
10. 11 consideration answers:
5. Check Box3: Off
6. Check Box1: Off
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10. Check Box7: Off
11. Check Box9: Off
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43. APPRAISAL SUMMARY:

Contents lists available at ScienceDirect

Psychiatry Research

journal homepage: www.elsevier.com/locate/psychres

A randomized controlled trial of mindfulness in patients with schizophrenia✰

Kun-Hua Lee Department of Educational Psychology and Counseling, National Tsing Hua University, 521 Nan-Da Road, Hsinchu City 30014, Taiwan

A R T I C L E I N F O

Keywords: Mindfulness Negative symptoms PANSS Schizophrenia GEE

A B S T R A C T

Cognitive Behavioral Therapy (CBT) is frequently used to attenuate the severity of positive schizophrenia symptoms; however, few studies have focused on attenuating negative symptoms. Recently, researchers have become interested in the effects of mindfulness-based intervention (MBI) on schizophrenia, but the lack of evidence-based results from random clinical trials (RCTs) has limited their effectiveness. Moreover, longitudinal data must be examined using appropriate study designs. We recruited 60 schizophrenia patients and randomly assigned them to an MBI or to a treatment-as-usual group. Negative symptoms, positive symptoms, mindfulness, and depression were assessed at baseline, post-course, and at a 3-month follow-up. Descriptive analysis and generalized estimating equations (GEEs) were used to examine the effects of MBI. We found that MBI mitigated the severity of negative symptoms and of general schizophrenic psychopathology except for the positive symptoms and for those of depression. Unexpectedly, we did not find long-term effect of mindfulness on negative symptoms. Larger sample sizes, long-term practical course, more rigorous study procedures, and a double-blind design should be considered in future studies.

1. Introduction

The lifetime prevalence of schizophrenia has been estimated to be 0.4% (Saha et al., 2005), and for decades schizophrenia has been considered and treated as a severe mental disease. Simeone et al. (2015) reported that the median prevalence of schizophrenia in 2014 was 0.33%, and that the worldwide lifetime prevalence was 0.49%. The overall prevalence in China ranged between 0.044% and 0.066% (Long et al., 2014). The prevalence of schizophrenia has been stable throughout the past few decades, and because the disease is extremely burdensome to schizophrenia patients and their caregivers (Hsiao and Tsai, 2014), efficacious treatments should be a biomedical priority. Better therapies would give patients and their caregivers more con- fidence about how to maintain a balanced and healthy lifestyle and, undoubtedly, more motivation to actually do it.

Cognitive Behavioral Therapy (CBT) is a strongly recommended management strategy for schizophrenia (Brus et al., 2012). CBT was originally developed to ameliorate depression and anxiety, and it was assumed that depression and its sequelae were maladaptive beliefs caused by disturbing life events (Roth et al., 2002). To treat schizo- phrenia, CBT was modified to focus on the beliefs about the symptoms and on how to cope with them by guiding the questions (Dickerson and Lehman, 2011). Evidence confirms that CBT has a strong attenuating

effect on the severity of positive symptoms in patients with acute schizophrenia, but that it has only a small-to-moderate effect on the relapse of positive and negative symptoms (Hoffman et al., 2012). Ef- fective schizophrenia intervention should focus on subjective well- being and quality of life, increased functional performance, and pre- venting relapses (Dickerson and Lehman, 2011).

More evidence that supports the beneficial effects of mindfulness- based intervention (MBI) on schizophrenia is accumulating (Khoury et al., 2013). Of five patients with severe schizophrenia who underwent eight MBI sessions and regular daily meditation for eight months, all reported significant mitigation in the severity of their hal- lucinations and delusions (Sheng et al., 2018). Moreover, a cross-sec- tional study (Dudley et al., 2018) reported that a higher extent of mindfulness attenuated distress when patients heard voices, and that self-compassion partially mediated between mindfulness on the severity of voices and distress. This indicates that mindfulness can be important for reducing the severity of symptoms and for increasing quality of life and subjective well-being.

MBI is a kind of psychological and behavioral practice based on Buddhist meditation, and it focuses on the awareness that emerges through purposely and nonjudgmentally paying attention in the present moment to the moment-by-moment unfolding of experience (Kabat- Zin, 2003). Practitioners of MBI for schizophrenia claim that its patients

https://doi.org/10.1016/j.psychres.2019.02.079 Received 28 November 2018; Received in revised form 1 February 2019; Accepted 1 February 2019

✰Conflict of Interest: Kun-Hua Lee has no conflicts of interest related to this study. E-mail addresses: [email protected], [email protected].

Psychiatry Research 275 (2019) 137–142

Available online 19 March 2019 0165-1781/ © 2019 Elsevier B.V. All rights reserved.

T

have reported relaxation, relief from psychological symptoms, cognitive change, and focus on the present (Brown et al., 2010). Schizophrenia patients developed emotions and beliefs that were more adaptive, and they said that MBI motivated them to more closely maintain balanced and healthy lifestyles (Tabak et al., 2015). However, many questions about the efficacy of MBI and the mechanism of mindfulness on schi- zophrenia await resolution (Chadwick, 2014).

Although confirmatory evidence of the benefits of MBI for schizo- phrenia patients is currently being reported by randomized clinical trials (RCTs), there are limits to its ability to attenuate schizophrenia symptoms, especially negative symptoms (Cramer et al., 2016). In Hong Kong, a larger-scale (n=107) RCT on the effects of MBI on schizo- phrenia patients showed significantly ameliorated positive and negative symptoms after six months compared with patients who underwent only treatment-as-usual (TAU) (Chien and Thompson, 2014).

In the past, the paired t-test and analysis of variance (ANOVA) were frequently used to evaluate follow-up and longitudinal data. However, ANOVA and repeated measurements could not precisely present the changes of an individual to limit the effectiveness of intervention (Zeger et al., 1988). Generalized Estimating Equations (GEEs) can be used to analyze normal and non-normal data in RCTs and longitudinal studies (Bell et al., 2018). In the present study, we not only examined the effectiveness of mindfulness-based intervention on negative symp- toms and psychotic symptoms, but also profiled the trend of changes in outcome measures on schizophrenia. Thus, we used GEEs to analyze our follow-up data.

In sum, the present study aimed to use randomly assigned and GEE analyses to examine the effect of MBI on the severity of psychotic symptoms in schizophrenia patients. We hypothesized that:

(1) At baseline, there would be no significant differences in the seve- rities of positive symptoms, negative symptoms, general psychotic symptoms, and depression between the MBI and TAU groups.

(2) At baseline, there would be no significant differences in the extent of mindfulness between the MBI and TAU groups.

(3) Post-course, the severity of positive and negative symptoms in the MBI group would be significantly lower than in the TAU group.

(4) Post-course, the extent of mindfulness in the MBI group would be significantly higher than in the TAU group.

(5) At the 3-month follow-up, the severity of positive and negative symptoms in the MBI group would be significantly lower than in the TAU group.

(6) At the 3-month follow-up, the extent of mindfulness in the MBI group would be significantly higher than in the TAU group.

2. Methods

2.1. Study design

This RCT examined the effects of MBI on schizophrenia patients. PANSS scores at baseline, post-course, and follow-up between the MBI and TAU groups have been analyzed using repeated measures (Hsieh et al., 2018).

2.2. Patients and procedures

We recruited 60 schizophrenia patients from rehabilitation wards and daycare centers in mental hospitals in eastern Taiwan. All were referred by psychiatrists, nurses, occupational therapists, clinical psy- chologists, or volunteers. Yuli Hospital's Institutional Review Board approved the study protocol (YLH-IRB-10307). Inclusion criteria were (a) being 18–65 years old, (b) being diagnosed on the schizophrenia spectrum, (c) being able to read and write Taiwanese Mandarin Chinese, and (d) having at least an elementary school education. Patients with (a) psychotic symptoms, (b) delirium, or (c) extensive suicidal ideation, or (d) patients who were violent were excluded.

The research assistant stated the purpose of this project and ex- plained each patient's personal rights and potential risks before they signed a written informed consent. Patients were then randomly as- signed to the mindfulness group (MBI; n=30) or to the treatment-as- usual group (TAU; n=30). Before undergoing MBI, the baseline se- verity of the positive and negative symptoms, and the extent of the mindfulness, were all assessed. The research assistant was responsible for the interview and assisted participants on the completion of the self- report questionnaires. Two assessors were trained by experienced clinical psychologists. Before assessing, the principal researcher as- sessed the same participant with the assessors and discussed any in- consistent scores in order to improve the consensus. The same assess- ments were made after eight weeks of MBI and at the three-month follow-up. The CONSORT flowchart is shown in Fig. 1.

2.3. Interventions

2.3.1. Mindfulness-based interventions We developed an eight-session, 1.5-h weekly MBI program for

schizophrenia based on a self-awareness, self-regulation, and self- transcendence (S-ART) model of mindfulness (Vago and Silbersweig, 2012). S-ART assumes that mindfulness practice effica- ciously regulates the behaviors, increases the awareness, and maintains a positive relationship between each patient's self and others. In the present study, the eight weeks of MBI primarily focused on practicing self-awareness and self-regulation. Three groups were led by six senior clinical psychologists who had undergone a 3-day MBI workshop and maintained daily mindfulness practice. During the 3-day workshop, trained therapists were taught the concepts of mindfulness, mindfully eating, mindfully walking, mindful yoga, mindful meditation, and

Fig. 1. CONSORT flowchart. *: The participants who did not complete at least four sessions were treated as the participants who failed to intervention.

K.-H. Lee Psychiatry Research 275 (2019) 137–142

138

mindful self-compassion. After the workshop, they were asked to practice mindfulness daily throughout the week.

In the first week, patients were introduced to the concept of mindfulness and asked to meet the expectations of the MBI group. Homework was assigned at the end of each session. The second week, we invited the patients to play simple puzzle games to stimulate their curiosity. We then taught them a 15-min breathing mediation, which was assigned as daily homework. The third week, we invited the pa- tients to mindfully write their name after their homework review. The fourth week, we taught them to mindfully eat and to allow themselves to experience the effect of habitual behaviors after their homework review. The fifth week, we asked the patients to mindfully read and write a short paper. In the sixth and seventh weeks, we asked them to mindfully stretch. The eighth week, we taught them self-compassionate meditation to increase their capacity for self-care and prosocial beha- vior. Each week, a 15-min breathing meditation was done before we gave the patients feedback and their homework assignment.

2.3.2. Treatment-as-Usual All of our participants were recruited from rehabilitation wards and

daycare centers. Before entering this study, all of the participants with residual symptoms were treated with routinely scheduled rehabilita- tions, such as, walking 5000 steps every morning, occupational re- habilitation twice a week, nutrition counseling, nursing care, health education group, mild doses of antipsychotic drugs, and other routine mental hospital activities. Thus, the participants in the TAU group were asked to maintain their routine activities.

2.4. Measurements

2.4.1. Personal information: included ID, gender, age, and length of formal education 2.4.1.1. Chinese version of the mindfulness attention awareness scale (MAAS). This scale was developed by Brown and Ryan (2003) to assess the extent of dispositional mindfulness. It is sensitive to improvements in the extent of a patient's mindfulness. Chang et al. (2011) translated the MAAS into Chinese and reported that it had good reliability and validity. It assesses fifteen items rated from 1 (Never) to 6 (Always). Higher scores mean a lower level of mindfulness.

2.4.1.2. Beck depression inventory (BDI-II). The scale was developed to assess the severity of depressive symptoms (Beck et al., 1988). There are 21 items rated from 0 to 4 that ask about different depression symptoms. Higher scores mean more severe depressive symptoms (Walter et al., 2003). Cronbach's α of the BDI-II after 8 sessions in this study was 0.90.

2.4.1.3. Scale for assessment of negative symptoms (SANS). The scale was developed by Andreasen (1982) to assess the severity of negative symptoms. Twenty-three items are rated from 0 (None) to 5 (Severe). Higher scores mean more severe negative symptoms. The reliabilities of the five subscales were: affective flattening (0.86), alogia (0.89), avolition (0.68), anhedonia (0.74), and attention impairment (0.86) (Andreasen et al., 2003).

2.4.1.4. Chinese Mandarin version of the positive and negative syndrome scale (CMV-PANSS). The PANSS includes 30 items rated from 1 to 7 that assess the severity of the positive and negative symptoms and of the general psychopathology of patients with schizophrenia. Higher scores mean more severe symptoms. The CMV-PANSS showed good reliability (Cronbach's α=0.928) (Wu et al., 2015).

2.5. Statistical analysis

Intention to treat analysis (ITT) was used in the present study for

two reasons (Gupta, 2011). First, ITT ignores noncompliance and withdrawal. Second, ITT preserved sample size in the present study. Our sample was small because it was difficult to recruit patients. De- scriptive analyses, t-tests, and χ2 tests were used to determine the dis- tributions of demographic and outcome variables in the two groups. Generalized Estimating Equations (GEEs) are frequently recommended for analyzing longitudinal data when the data are not normally dis- tributed and the variance of the outcome variables are not constant (Ghisletta and Spini, 2004). In the present study, GEEs were used to examine pre-course, post-course, and follow-up data. Significance was set at p < 0.05.

3. Results

3.1. Demographic data

Only 50 of the recruited patients completed the study: 3 dropped out because of occupational training, 3 contracted influenza A infec- tion, 3 dropped out for personal reasons, and 1 had an acute psychotic episode before the intervention (see Fig. 1). The mean age of MBI group members was 54.43 ± 6.32 years and of TAU group members was 51.15 ± 6.32 years. There were no significant differences in the se- verity of SANS (t= ‒1.649, df= 56, p=0.105), PANSS (t= ‒0.788, df= 55, p=0.434), depressive symptoms (t=0.296, df= 56, p=0.768), or the level of mindfulness (t=0.566, df= 56, t=0.574) between dropouts and patients who completed the study, except for age (t= ‒3.313, df= 57, p=0.002).

At baseline, there were no significant differences between the MBI and TAU groups in sex (χ2= 1.482, df= 1, p=0.223) or educational level (χ2= 6.663, df= 4, p=0.155), but TAU group members were significantly older than were the MBI group members (t=2.722, df= 57, p=0.009). There were no significant differences in outcome measures between the MBI and TAU groups in PANSS (t= ‒0.388, df= 55, p=0.699), SANS (t= ‒0.947, df= 56, p=0.347), level of mindfulness (t= ‒1.793, df= 56, p=0.078), and depressive symp- toms (t= ‒0.610, df= 56, p=0.545) (Table 1).

3.2. GEE data

We treated age as a covariant because of the significant difference in age between the MBI and TAU groups.

3.2.1. The effects of mindfulness-based intervention on negative symptoms GEE analysis showed a significant main effect of group on SANS

(β=0.661, p=0.011) and a significant main effect of time on SANS at time 1 (β=0.986, p=0.000). The effect of group× time on SANS reached was significant after baseline (β= ‒0.973, p=0.000) but not significant after the post-course (β= ‒0.1, p=0.53).

The main effects of group (β=0.996, p=0.000) and at time 1 (β=0.508, p=0.011) were als