The efficacy of extended metacognitive training for psychosis: A randomized controlled trial

SCHRES-08437; No of Pages 9 Schizophrenia Research xxx (xxxx) xxx

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The efficacy of extended metacognitive training for psychosis: A randomized controlled trial Ryotaro Ishikawa a,⁎, Takuma Ishigaki b, Takeshi Shimada c, Hiroki Tanoue d,e, Naoki Yoshinaga f, Naoya Oribe g, Takafumi Morimoto h, Takeshi Matsumoto i, Masahito Hosono b a

Department clinical psychology, Taisho University, Japan Graduate School of Arts and Sciences, University of Tokyo, Japan Mental Support Soyokaze Hospital, Japan d Graduate School of Medicine and Veterinary Medicine, University of Miyazaki, Miyazaki, Japan e School of Nursing, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan f Organization for Promotion of Tenure Track, University of Miyazaki, Japan g National Hospital Organization Hizen Psychiatric Center Department of Neuropsychiatry, Graduate School of Medical Sciences, Kyushu University, Japan h Sapporo Medical University, Japan i Oouchi Hospital, Japan b c

a r t i c l e

i n f o

Article history: Received 26 March 2019 Received in revised form 30 July 2019 Accepted 3 August 2019 Available online xxxx Keywords: Metacognitive training Schizophrenia Randomized controlled trial Japan Cognitive theory for psychosis

a b s t r a c t This study investigated the efficacy of 10-module metacognitive training (MCT) among Japanese patients with schizophrenia by conducting a multicenter randomized controlled trial to test the influence of the most recent and extended version of MCT on positive symptoms. A six-center, randomized, assessor-blind, controlled trial between “treatment as usual” (TAU) and TAU + MCT was conducted. Fifty inpatients and outpatients with schizophrenia, schizotypal, and delusional disorders (ICD 10) were enrolled, then randomly assigned to TAU (n = 26) or TAU + MCT (n = 24). Assessments were made at baseline, after six weeks, immediately posttreatment, and 1month post-treatment. The primary outcome was positive symptom score, as measured by the Positive and Negative Syndrome Scale (PANSS). General assessment of functioning (GAF) and measures of cognitive biases were secondary outcomes. Completion at post-treatment (10 weeks later) and 1-month follow-up was high—TAU + MCT, n = 22 (91.67%) and TAU, n = 23 (88.46%). The severity of PANSS positive symptoms declined significantly in the TAU + MCT treatment group compared with the TAU group. GAF also showed significantly greater improvement in the TAU + MCT group compared with the TAU group. There was also a trend for greater efficacy of MCT on cognitive biases. In conclusion, this study provides support for the efficacy of 10 module MCT concerning positive symptomatology (especially, delusion) and general functioning. © 2019 Elsevier B.V. All rights reserved.

1. Introduction Schizophrenia-related disorders are a common form of psychosis. In acute episodes, delusions and hallucinations can cause people to disconnect from reality. People with a diagnosis of schizophrenia die an average of 14.5 years earlier than do those without diagnosed schizophrenia (Hjorthøj et al., 2017). While antipsychotic medication is common, its efficacy has been debated, as second-generation (or atypical) antipsychotics have not lived up to the initial high expectations (Kendall, 2011). Specifically, they exert only a moderate effect size relative to placebos on primary positive symptoms, and relapses occur in approximately one-quarter of all patients (Leucht et al., 2003, 2009). ⁎ Corresponding author at: Department Clinical Psychology, Taisho University, 3-20-1, Nishi-Sugamo, Toshma-Ku, Tokyo, Japan. E-mail address: [email protected] (R. Ishikawa).

Diverse psychological approaches—especially cognitive behavioral therapy (CBT)—have increasingly been adopted as complementary strategies to antipsychotic medication (Sivec and Montesano, 2012; Wykes et al., 2008). CBT for psychosis (CBTp) highlights the beliefs and cognitive biases related to delusion and hallucination. According to CBTp, cognitive biases are distortions in the collection, appraisal, and processing of information (e.g., jumping to conclusions; JTC). The JTC bias refers to the tendency to make decisions based on very little information, thereby increasing the likelihood of a hasty formation of inaccurate beliefs (Dudley et al., 2016; Ross et al., 2015). A metaanalysis (Mehl et al., 2015) investigated whether CBTp is an effective intervention for reducing delusions. Mehl and colleagues reported a small but significant effect size for CBT in comparison to treatment-as-usual (TAU). In addition to CBTp, an example of a novel intervention based on the cognitive theory for psychosis is metacognitive training (MCT). MCT is

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Please cite this article as: R. Ishikawa, T. Ishigaki, T. Shimada, et al., The efficacy of extended metacognitive training for psychosis: A randomized controlled trial, Schizophrenia Research, https://doi.org/10.1016/j.schres.2019.08.006

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theory-driven, standardized, and manualized group training for individuals with schizophrenia (Moritz and Woodward, 2005, 2007). It aims to increase cognitive awareness (meta-level) by providing psychoeducation on cognitive biases, such as JTC, followed by specific, structured, cognitive exercises. MCT could enrich the repertoire of problem-solving strategies and encourage patients to critically reflect on the consequences of cognitive biases. MCT is grounded on the principles of CBT (Fowler et al., 1995) and basic research on cognitive biases in schizophrenia (for a review, see Garety and Freeman, 1999). Compared to CBT, MCT is more structured and utilizes multiple cognitive tasks (e.g., remembering picture details, deducing titles from paintings), focusing on attenuating overconfidence in errors rather than accuracy. Although MCT can be considered a variant of CBT, the main difference is its approach to raise awareness about cognitive biases via cognitive exercises and tasks (Moritz et al., 2011a, b). For example, patients should personally experience cognitive biases rather than just being informed about their dysfunctionality. Meta-analyses have demonstrated that MCT reduces the positive symptoms of schizophrenia (Eichner and Berna, 2016; Liu et al., 2018; Philipp et al., 2018). Cognitive bias due to JTC appear to contribute to delusions (Garety et al., 1991; Sartup et al., 2008), and MCT is particularly effective in reducing delusions, as it targets cognitive biases related to delusions, like JTC (Pankowski et al., 2016). However, some training and psychoeducation in MCT modules have aimed to reduce not only delusions but also hallucinations (e.g., modules about attributional style), and a randomized controlled trial (RCT) by Briki et al. (2014) showed that MCT reduced hallucination severity. MCT can effectively reduce not only cognitive bias such as JTC but also cognitive insight (Pankowski et al., 2016). Cognitive insight is the ability of people with psychosis to evaluate and correct their distorted beliefs and misinterpretations (Beck et al., 2004). There is some evidence that people with a psychosis experiencing delusions have lower cognitive insight than do healthy controls (Beck et al., 2004; Guerrero and Lysaker, 2013). Although the original MCT contained eight modules (e.g., Eichner and Berna, 2016), a 10-module MCT was recently developed by the University Medical Center Hamburg-Eppendorf (see www.uke.de/mkt for the full list of languages). The additional two modules include the themes, “improving low self-esteem” and “normalization and ways to deal with stigma.” These developers expect these additional modules to reduce psychotic symptoms for several reasons. First, many people with (paranoid) schizophrenia have low self-esteem (Freeman et al., 1998; Moritz et al., 2010; Sundag et al., 2015), which, has been theorized by some to be etiologically linked with paranoia (Kesting and Lincoln, 2013). In the “self-esteem” module, participants can learn to focus less on the negative aspects of their lives and perceived personal flaws and instead identify and appreciate the aspects that are going well. Further, many psychiatric disorders, including schizophrenia (Gerlinger et al., 2013; Świtaj et al., 2015), are subject to prejudice and associated with stigma, contributing to further problems (e.g., insecurities, depression), which, in turn, can promote symptoms of psychotic disorders. For example, some studies suggested the possibility that the relationship between perception of stigmatization and symptoms is a vicious circle in which the elements reinforce each other (Ertugrul and Uluğ, 2004; Lien et al., 2015). The “dealing with prejudices (stigma)” module attempts to minimize self-stigma by increasing awareness of the prevalence of mental illness in the general population. It is emphasized that mental illness/psychosis does not determine one's worth and teaches participants how to appropriately deal with their illness. Cognitive theory for psychosis and MCT were developed in the West; however, they are widespread in Eastern cultures. For example, Ishikawa et al. (2017) investigated the relationships between cognitive biases and symptoms of schizophrenia and showed that cognitive biases appear specifically related to positive symptoms. These results indicated that the cognitive theory for psychosis could apply to Japanese patients

and suggested that cognitive interventions that target patients' prominent biases can help improve positive symptoms in Japanese patients with schizophrenia. Thus, a Japanese-translated version of the MCT could also effectively address the positive symptoms of patients with schizophrenia in Japan. The MCT-J network (http://www.mct-j.net/) is an association for practitioners and researchers for MCT in Japan. Founded in 2013, it aims to disseminate MCT across psychiatric medical fields in Japan and to train skilled MCT therapists. The MCT-J network has held workshops to disseminate MCT and to regularly increase the number of MCT practitioners across Japan. As of December 2018, N1000 practitioners and researchers are enrolled in this network. In addition to clinical practice, various collaboration studies using the MCT-J network have been conducted to test the feasibility and efficacy of MCT (Hosono et al., 2013) and the cognitive theory of psychosis (Ishikawa et al., 2017). However, an RCT examining MCT among the Japanese population has never been conducted. This study investigated the efficacy of MCT among Japanese patients with schizophrenia by conducting a multicenter RCT. In sum, a 10module MCT was recently developed; however, its efficacy has not been verified in clinical settings, making this study the first RCT to evaluate the efficacy of this version of MCT. We hypothesized that participants receiving MCT would show improvements in positive symptoms (primary outcome). While MCT is more effective in reducing delusions than hallucinations (Pankowski et al., 2016), some training and psychoeducation provided in MCT aim to reduce both delusions and hallucinations. Previous studies have used positive symptoms scores, including delusion and hallucination, as primary outcomes (Briki et al., 2014; Favrod et al., 2014; Kumar et al., 2010; Moritz et al., 2014a, b); therefore, we used a positive symptoms scale on Positive and Negative Syndrome Scale (PANSS; Kay et al., 1987) as our primary outcome. Additionally, we examined the efficacy of MCT for delusions, as well as for hallucinations. For this, we assessed the severity of delusions and hallucinations using sub-items from the PANSS. Further, as secondly outcomes we examined the efficacy of MCT on JTC biases, cognitive insight, general functioning, quality of life (QOL), depression, and self-esteem. JTC biases and cognitive insight are cognitive factors that promote delusion, and a narrative systematic review showed that MCT could improve both JTC and cognitive insight (Pankowski et al., 2016). Consequently, we examined the efficacy of MCT on JTC biases and cognitive insight. Moreover, our additional two modules focused on low self-esteem and negative mood (e.g., depression). We tested the hypothesis that our MCT, which included additional modules, can improve low self-esteem and depression. In addition, a systematic review (Pankowski et al., 2016) suggested that a prospective study that examined patients' functioning after MCT was needed. For this, we tested whether MCT improved participants' general functioning and QOL.

2. Methods 2.1. Procedure and design Following a baseline assessment, patients were randomly allocated to either a “TAU” condition or the “TAU + MCT” condition in a 1: 1 ratio using the minimization method balancing on primary outcome score (PANSS positive symptoms scale) (see Fig. 1). Random assignments were performed by independent researchers who were not access to patient's information. After the baseline assessment, they were reassessed after six weeks (mid-assessment) and 10 weeks (post-assessment). For follow-up, all participants were reassessed 1-month after the post-assessment. Assessors were blind to treatment allocation to prevent the Rosenthal effect (Rosenthal and Rubin, 1978). This study was approved by the ethics committee of the University of Tokyo, Japan (no. 519) and the ethics committee or responsible

Please cite this article as: R. Ishikawa, T. Ishigaki, T. Shimada, et al., The efficacy of extended metacognitive training for psychosis: A randomized controlled trial, Schizophrenia Research, https://doi.org/10.1016/j.schres.2019.08.006

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Fig. 1. CONSORT flow chart. MCT: meta cognitive training; TAU: treatment as usual; PANSS: Positive and Negative Syndrome Scale.

individual at each mental health service institution (registration no. UMIN000027301). 2.2. Participants We enrolled patients from all six psychiatric hospitals in Japan: Mental Support Soyokaze Hospital, Oouchi Hospital, Sapporo Hanazono Hospital, Hizen Psychiatric Center, Taniguchi Hospital, and Wakakusa Hospital. To recruit participants, we asked care providers (e.g., psychiatric nurses, social workers) at each hospital to inform patients about this MCT trial. Patients who wanted to participate contacted us through their care provider, and we obtained patients' written informed consent along with their demographic and clinical information. In the informed consent, we stated that participants who missed more than three sessions (i.e., non-completers) could no longer participate in the study. Further, we restrict patients from accessing CBTp until after the follow-up period. We aimed to enroll total 50 patients who met the following inclusion criteria, which were based on previous RCTs for MCT (Briki et al., 2014; Gawęda et al., 2015; Moritz et al., 2011a, b): a diagnosis of schizophrenia, schizotypal and delusional disorders (ICD 10 criteria,

F20–29) by a psychiatrist; aged 20–60 years; and an in- or outpatient. The Mini-International Neuropsychiatric Interview (Sheehan et al., 1998) was administered to confirm the patients meet criteria of “psychotic disorder”, and a minimal symptom threshold for inclusion was defined as N2 on the Delusion component of the PANSS. Patients with an intellectual disability, developmental disorder, dementia, personality disorder, organic brain damage, or history of substance abuse were excluded. Additionally, following Moritz et al. (2013), patients who scored ≥ 5 on the PANSS hostility item, or ≥6 on the suspiciousness item were excluded, as they were often unable to attend group sessions, which could negatively impact group coherence. If a participant was absent more than three times during the 10-module MCT, they were excluded as “non-completers.” Non-completer could no longer attend. Consequently, all completer in the MCT + TAU condition received at least eight modules. For intent-to-treat (ITT) analyses, based on Moritz et al. (2013), multiple imputation was adopted to estimate mid-assessment, posttreatment, and follow-up scores for non-completers (i.e., no reassessment data available). Seventy-eight patients were initially recruited (see Fig. 1.); however, 28 patients were excluded for not

Please cite this article as: R. Ishikawa, T. Ishigaki, T. Shimada, et al., The efficacy of extended metacognitive training for psychosis: A randomized controlled trial, Schizophrenia Research, https://doi.org/10.1016/j.schres.2019.08.006

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meeting inclusion criteria (screening-to-inclusion ratio = 64%). All patients were reimbursed (8000 yen) for their participation.

preferences to be elicited. The scale has acceptable psychometric properties and internal consistency (Cronbach's alpha = 0.71; Abdin et al., 2019).

2.3. Psychopathological assessment Assessments of the PANSS and General Assessment of Functioning (GAF) were conducted using semi-structured interviews by assessors who are practitioners of clinical psychology, psychiatric nurses, or occupational therapists who were blind to treatment allocation. Before the trials, all assessors were trained using video demonstrations. The same rater interviewed the same patient throughout the trial period. Other assessments were conducted using self-reported measurements. 2.3.1. PANSS Symptom severity was assessed with the PANSS (Kay et al., 1987), which was translated into Japanese. All ratings followed semistructured interviews. The PANSS has acceptable psychometric properties and internal consistency (Cronbach's alpha = 0.73–0.83) and is sensitive to change (Kay et al., 1987; Santor et al., 2007). Reliability of the Japanese version of the PANSS was confirmed (Yamada et al., 1993; Igarashi et al., 1998). Since metacognitive interventions primarily target positive symptoms, we assessed only the positive symptoms subscore (the sum of the delusions (P1), conceptual disorganization (P2), hallucinatory behavior (P3), grandiosity (P4), excitement (P5), and suspiciousness/persecution (P6) items). We used the PANSS positive symptoms scale score as the primary outcome for this RCT. 2.3.2. GAF GAF is a well-known scoring system for mental illness severity and assesses Axis V of the DSM-IV-TR (American Psychiatric Association, 2000), which measures patients' psychological, social, and occupational functioning, ranging from mental well-being to severe psychopathology. The GAF was assessed for all groups. 2.3.3. Cognitive biases questionnaire for psychosis (CBQp) The CBQp (Peters et al., 2014) consists of 30 vignettes of everyday scenarios. Participants are asked to imagine themselves in a given situation and then to choose one of four cognitive responses. The scales assess five types of cognitive biases: intentionalizing, catastrophizing, dichotomous thinking, JTC, and emotion-based reasoning. We used it to assess JTC and other cognitive biases. The Japanese version of the CBQp has adequate validity and reliability, including internal consistency (Cronbach's alpha = 0.72; Ishikawa et al., 2017). 2.3.4. Beck cognitive insight scale (BCIS) Cognitive insight was measured with the BCIS, developed by Beck et al. (2004). It is a 15-item self-report scale. The BCIS measures cognitive insight in schizophrenia, and consists of two factors: selfreflectiveness (i.e., cognitive flexibility), which assesses individuals' beliefs that they may be wrong at times and their willingness to admit it; and self-certainty (i.e., overconfidence), which assesses individuals' beliefs that they are definitely correct about their decisions and experiences. The Japanese version of the BCIS (Uchida et al., 2009) is valid and reliable, with acceptable internal consistency (Cronbach's alpha = 0.67–0.78). 2.3.5. Beck depression inventory version 2 (BDI-II) The BDI-II is a 21-item self-report measure that assesses depressive symptoms (Beck et al., 1996). The Japanese version of BDI-II is valid and reliable, with good internal consistency (Cronbach's alpha = 0.87; Kojima et al., 2002). 2.3.6. 5-level EQ-5D (EQ-5D-5 L) The EQ-5D-5L (van Hout et al., 2012) is a well-known generic QOL measure and is advantageous because it allows for health-state

2.3.7. Self-esteem Participants completed the 10-item Rosenberg Self-esteem Scale (RSES; Rosenberg, 1965). The Japanese version is valid and reliable, displaying high internal consistency (Cronbach's alpha = 0.87; Mimura and Griffiths, 2007). 2.4. Treatments 2.4.1. TAU TAU included pharmacotherapy provided by a primary psychiatrist. Additionally, participants could voluntary attend a supportive therapeutic program, which included psychoeducation, computer training, and social activities. There was no CBTp-based intervention in the TAU condition. 2.4.2. TAU + MCT condition In this condition, patients underwent MCT in addition to TAU, using a Japanese version of MCT (Ishigaki, 2012) with eight standard and two additional modules. MCT sessions were administered once weekly during daily clinical practice and took around 10 weeks for all 10 modules. The participants in the TAU + MCT condition received a maximum of 10 modules before the post-treatment assessment. Generally, MCT is full, two-cycles (i.e., 16 modules) program; however, some research indicated that one 8-module MCT was effective for reducing psychosis symptoms (Erawati et al., 2014; Favrod et al., 2014; Gawęda et al., 2015; Kumar et al., 2010; Lam et al., 2015); therefore, we decided to utilize the onecycle MCT (eight modules) with two additional modules (total 10 modules). Further, in daily clinical psychiatry practice in Japan, psychological programs are generally conducted once a week, making it important to test the efficacy of MCT conducted on a weekly basis if MCT is to be disseminated in Japan. All MCT was delivered as a group intervention. Group facilitators were clinicians who regularly worked at the facility where the trial was conducted. They learned MCT practical skills in a workshop held at the MCT-J network and received supervision. The supervisor (second author) is a psychiatrist with expertise in MCT practice and research, who was instructed by Steffen Moritz, who developed the original manual for MCT. The number of participants per group across site and facilitator certification is shown in Table 1. This clinical trial was conducted in a clinical setting; therefore, in addition to the participants of this trial, some patients who were not participants attended the MCT group. The number of patients in each group ranged from three to seven, based on the MCT manual guidelines (see www.uke.de/mct). Missed sessions could not be repeated. Each session lasted 45–60 min and adhered to the study protocol and the manual's guidelines. 2.5. Statistical analyses Statistical procedures were performed using SPSS Version 25.0 (IBM Corp, 2017). Statistical analyses and reporting were conducted following CONSORT guidelines, with the primary analyses based on the ITT principle, which considered data from all participants whose baseline data were available. Multiple imputation was adopted to estimate mid-assessment, post-treatment, and follow-up scores for noncompleters (e.g., those who had missed 3 MCT sessions, or those who decline to participate in the TAU condition). Additionally, we also conducted per-protocol (PP) analyses, which refers to inclusion in the analysis of only those patients who strictly adhered to the protocol. The main results were computed using analyses of covariance (ANCOVA) that controlled for baseline scores. Differences between baseline (pre-

Please cite this article as: R. Ishikawa, T. Ishigaki, T. Shimada, et al., The efficacy of extended metacognitive training for psychosis: A randomized controlled trial, Schizophrenia Research, https://doi.org/10.1016/j.schres.2019.08.006

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Table 1 Number of participants per group and site. Site

Participants in TAU + MCT

Hanazono hospital Hizen psychiatric center MSS hospital–1st group MSS hospital–2nd group MSS hospital–3rd group Oouchi hospital Taniguchi hospital Wakakusa hospital

4 outpatients 3 outpatients 1 out and 4 inpatients 3 inpatients 3 inpatients 2 inpatients 2 outpatients 2 outpatients

Facilitators

Participants in TAU

OT Psychiatrist OT OT OT OT Psychiatric nurse Psychiatric nurse

4 outpatients 2 outpatients, 1 both 5 inpatients 1 outpatient, 1 both 2 in and 1 outpatient 2 inpatients 4 outpatients 3 outpatients

Note. MCT: meta-cognitive training, OT: occupational therapist, TAU: treatment-as-usual, MSS: Mental Support Soyokaze.

test) and post-test or follow-up test scores were treated as dependent variables, treatment condition as a fixed factor, and baseline scores as covariates. This strategy is superior to analyses of variance and Student's t-tests (Borm et al., 2007), and it was used in previous MCT efficacy studies (e.g., Moritz et al., 2013). Partial η2 statistic was calculated for effect size.

participant comparisons in the TAU + MCT group significantly decreased from baseline–mid (p = .039), baseline–post (p b .0001), and baseline–follow-up (p b .001), but not in the TAU group (Table 3). Thus, PANSS positive symptoms declined significantly more in the TAU + MCT group than in the TAU group.

3. Results

3.4. Secondary outcome

3.1. Baseline characteristics

Concerning delusion score on PANSS (P1), a significant group difference in favor of the TAU + MCT emerged at baseline–post (F[1,47] = 9.45, η2 partial = 0.17, p = .006) and baseline–follow-up tests (F [1,47] = 10.60, η2 partial = 0.18 p = .006). Within-participant comparisons in the TAU + MCT group showed a significant difference for baseline–post (p = .005) and baseline–follow-up (p = .023), but not in the TAU group, indicating that the TAU + MCT condition was superior to TAU for improving delusions. These results indicated that delusion severity declined more in the TAU + MCT group than in the TAU group. Concerning hallucinations on PANSS (P3), the ANCOVA did not reveal any significant differences; however, in the PP analysis, the ANCOVA revealed a significant difference in favor of the MCT at baseline–follow-up (F[1, 42] = 11.97, η2 partial = 0.22, p = .001). Thus, the TAU + MCT condition was superior to the TAU in improving hallucinations, only for the PP analysis. Concerning JTC as measured by CBQp, the ANCOVA revealed a significant difference in favor of the MCT at baseline–follow-up (F[1, 47] = 4.55, η2 partial = 0.09, p = .039). Within-participant comparisons did not reveal any significant differences. For the other CBQp subscale, neither result was significant. Concerning the BDI-II, the ANCOVA showed no significant difference between the two groups. However, within-participant comparisons in the MCT group showed a marginally significant decrease from baseline–post (p = .062), but not in the TAU group. For GAF, a significant difference in favor of the TAU + MCT group emerged at baseline–follow-up (F[1, 47] = 7.76, η2 partial = 0.14, p = .008). Within-participant comparisons showed a significant difference at baseline–post (p = .012) and baseline–follow-up (p = .001), but not in the TAU group, indicating that general function showed greater improved most strongly in the TAU + MCT group than in the TAU group. For all other measurements (i.e., BCIS, EQ-5D-5 L, and RSES), no results were significant.

At baseline, no differences emerged between groups regarding sex, age, disease duration, educational level, PANSS positive symptoms (primary outcome), or chlorpromazine equivalent values (Table 2). 3.2. Completion Completion at post-treatment (10 weeks later) and 1-month followup was high (TAU + MCT, n = 22, 91.67%; TAU, n = 23, 88.46%) and did not significantly differ between groups (χ2[1] = 0.14, p = .71). 3.3. Primary outcome Outcome by treatment condition (TAU vs. TAU + MCT) and ANCOVA results are presented in Table 3. The ANCOVA examining PANSS with positive symptoms scores as dependent variables revealed a significant group difference in favor of MCT, which emerged during baseline–mid (F[1,47] = 5.13, η2 partial = 0.09 p = .047), baseline– post (F[1,47] = 10.46, η2 partial = 0.15, p = .006), and baseline– follow-up tests (F[1,47] = 15.15, η2 partial = 0.22, p = .001). Within-

Table 2 Baseline characteristics of the sample (N = 50). Variable

Gender Men Women Education level Junior high High school University/college Outpatient/inpatient Outpatient Inpatient Both Age (years) Disease duration (years) Positive symptoms (baseline) CPZ equivalent values

χ2

TAU + MCT (n = 24) n (%)

TAU (n = 26) n (%)

13 (54.2) 11 (45.8)

12 (46.2) 14 (53.8)

0.32

0.570

3 (12.5) 16 (66.7) 5 (20.8)

2 (7.7) 19 (73.1) 5 (19.2)

0.38

0.830

12 (50.0) 12 (50.0) 0 (0.0) M (SD) 46.04 (8.37) 19.58 (8.95) 23.46 (7.21)

15 (57.7) 9 (34.6) 2 (7.7) M (SD) 48.96 (8.54) 22.5 (8.48) 24.08 (6.11)

720.82 (402.27)

804.97 (505.32)

p-Value

2.69

0.260

t-Test 1.22 1.19 0.33

p-Value 0.23 0.58 0.74

2.31

0.14

Note. MCT: meta cognitive training; TAU: treatment as usual; CPZ: chlorpromazine.

3.5. Post-hoc power analysis A post-hoc power analysis was conducted with G*Power (Faul et al., 2007) given the present sample size (n = 50) for an ANCOVA with α = 0.05. We used the yielded effect size from the ANCOVA that examined PANSS with positive symptoms scores in baseline–follow-up tests as dependent variables (η2 partial = 0.22) since it was the primary outcome. Statistical power was above 0.90 (1 − β N 0.95), suggesting our sample had adequate statistical power.

Please cite this article as: R. Ishikawa, T. Ishigaki, T. Shimada, et al., The efficacy of extended metacognitive training for psychosis: A randomized controlled trial, Schizophrenia Research, https://doi.org/10.1016/j.schres.2019.08.006

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Table 3 Group differences across time on means and standard deviations (ITT analyses; multiple imputation for missing data). Variables

Positive symptoms

Delusion

JTC

BDI-II

GAF

Group

TAU TAU + MCT TAU TAU + MCT TAU TAU + MCT

M (SD)

Mean differences (95% Cl) across time and ANCOVAs

Baseline

Mid

Post

Follow up

Baseline-mid

Baseline-post

Baseline-follow up

24.08 (6.11)

23.47 (5.68)

22.76 (5.92)

23.80 (6.26)

0.61 (−0.93 to 2.15)

1.31 (−0.48 to 3.11)

0.28 (−2.13 to 2.69)

23.46 (7.21)

21.12 (5.69)

19.42 (5.21)

18.84 (5.45)

2.34 (0.81 to 3.87)

4.03 (2.32 to 5.75)

4.62 (2.77 to 6.47)

F = 5.13⁎, ηp2 = 0.09 0.45 (−0.23 to 1.13)

F = 10.46⁎⁎, ηp2 = 0.15 0.27 (−0.17 to 0.71)

F = 15.15⁎⁎⁎, ηp2 = 0.22 0.13 (−0.45 to 0.70)

4.19 (1.23)

3.74 (1.48)

3.92 (0.98)

4.07 (0.96)

3.88 (1.19)

3.37 (1.07)

3.12 (0.92)

3.10 (1.09)

0.51 (0.24 to 0.77)

0.75 (0.41 to 1.10)

0.78 (0.38 to 1.18)

F = 0.42, ηp2 = 0.01 0.10 (−0.68 to 0.87)

F = 9.45⁎⁎, ηp2 = 0.17 0.17 (−0.53 to 0.87)

F = 10.60⁎⁎, ηp2 = 0.18 −0.51 (−1.56 to 0.54)

9.94 (1.84)

9.85 (1.69)

9.78 (1.77)

10.45 (2.38)

10.55 (1.98)

10.28 (1.73)

9.80 (2.13)

9.55 (2.00)

TAU

13.19 (6.84)

11.26 (6.60)

10.35 (4.85)

13.83 (12.36)

TAU + MCT

13.14 (8.91)

11.02 (7.74)

10.04 (8.21)

9.72 (7.62)

TAU TAU + MCT

49.50 (13.92)

53.58 (11.26)

54.51 (12.90)

53.32 (12.15)

51.58 (8.51)

56.66 (8.09)

59.18 (6.43)

61.52 (7.40)

0.27 (−0.45 to 0.99)

0.76 (0.04 to 1.47)

1.00 (0.33 to 1.66)

F = 0.24, ηp2 = 0.00 1.92 (−0.54 to 4.39)

F = 0.70, ηp2 = 0.01 2.84 (0.76 to 4.92)

F = 4.55⁎, ηp2 = 0.09 −0.64 (−5.20 to 3.93)

2.12 (−0.57 to 4.82)

3.10 (0.54 to 5.66)

3.43 (0.67 to 6.18)

F = 0.05, ηp2 = 0.00 −4.08 (−9.35 to 1.20)

F = 0.06, ηp2 = 0.00 −5.01 (−10.64 to 0.61)

F = 2.57, ηp2 = 0.05 −3.82 (−9.54 to 1.90)

−5.07 (−8.11 to −2.04) F = 0.82, ηp2 = 0.02

−7.59 (−10.65 to −4.54) F = 2.13, ηp2 = 0.04

−9.94 (−14.00 to −5.87) F = 7.76⁎⁎, ηp2 = 0.14

Note. ITT: Intention-to-treat; MCT: Meta Cognitive Training; TAU: Treatment As Usual; PANSS: Positive and Negative Syndrome Scale; JTC: Jumping To Conclusions; BDI-II: Beck Depression Inventory; GAF: General Assessment of Functioning. + p b .1, ⁎p b .05; ⁎⁎p b .01, ⁎⁎⁎p b .001.

4. Discussion This was the first RCT to examine the efficacy of MCT among Japanese patients with schizophrenia using a 10-module program. 4.1. Primary outcome As expected, participants in the TAU + MCT group showed improvement in their PANSS positive symptoms after MCT when compared to the TAU condition, which was sustained after one month. Additionally, compared with prior meta-analyses (Eichner and Berna, 2016; Liu et al., 2018) that demonstrated that MCT exerts a moderate effect on delusions and positive symptoms, our results indicated a larger effect for positive symptoms (η2 partial = 0.22). The additional two modules may have affected the reduction of positive symptoms. These modules include sessions with themes such as “normalization and ways to deal with stigma,” which is a critical theme of MCT. The additional module about normalizing emphasizes that normalization may have been effective in alleviating positive symptoms. Second, the MCT therapists in this trial were clinicians who regularly worked where the trial was conducted. Therefore, each therapist may have already established a good relationship with participants, which could influence the effect size. Although MCT can be conducted regardless of qualification, it involves group psychotherapy; therefore, it is vital to establish a good treatment relationship. In future research, we will further examine the treatment relationships in MCT. Finally, the MCT-J network worked advantageously to ensure that the trial was performed. All therapists participated in a workshop held at the MCT-J network and had learned MCT practical skills. Thus, we could train MCT therapists who had sufficient skills, and the effect size we found further supports the validity of the MCT-J network as a therapist-training method. Additionally, our analysis revealed that the TAU + MCT condition was superior to the TAU condition in improving delusions. While hallucination severity did not show a significant decrease, the PP analysis showed that the TAU + MCT group showed improvement in their hallucinations, supporting the possibility that MCT can improve hallucinations although the effect would be limited and smaller in comparison to delusions. We discussed that the relationship between MCT and positive symptoms reduction would be more specific to delusional thinking

than hallucinations. Research has shown that MCT interventions target mainly cognitive biases related to delusions (i.e., JTC), so our findings were consistent with Pankowski et al. (2016). In addition, our results demonstrating the efficacy of MCT in a Japanese sample support the hypothesis that the “Western” cognitive model is culturally appropriate for non-Western cultures (Ishikawa et al., 2017). Previous research (Lam et al., 2015) also indicated that MCT was effective with patients in non-Western cultures.

4.2. JTC biases Concerning participants' cognitive bias, the analysis revealed a significant difference in favor of MCT at follow-up on JTC scores, but not on the CBQp total score. This result tentatively supports previous studies showing that MCT can improve JTC bias (Aghotor et al., 2010; Gawęda et al., 2015; Moritz et al., 2013; Moritz et al., 2014a; Moritz et al., 2011a; Ochoa et al., 2017). However, most research has studied the effect on objective JTC biases using the beads task, and we assessed only subjective JTC using CBQp. Cognitive biases assessed with self-report scales and performance-based assessments (e.g., beads task) may cover diverse aspects of cognitive biases (Gawęda et al., 2015; Peters et al., 2014). Subjective bias may be more closely associated with emotional processes, while objective bias may be more closely related to cognitive factors (Garety et al., 2005; Peters et al., 2014). Further research should address what bias may be more pertinent to the formation and maintenance of psychotic experiences and verify if MCT is effective for subjective or objective cognitive biases. A study by Gawęda et al. (2015) was similar to this study because they used CBQp to assess cognitive bias and found significant improvements in JTC as well as CBQp total score, catastrophizing, and emotionbased reasoning. We found a significant improvement only in JTC. The difference may be because of sample characteristics. For example, mean CBQp scores at baseline in the present study were lower than in Gawęda and colleagues. The severity of cognitive biases we reported was at “healthy levels;” therefore, their CBQp total scores and other cognitive biases subscale (e.g., catastrophizing) are less likely to change even after MCT.

Please cite this article as: R. Ishikawa, T. Ishigaki, T. Shimada, et al., The efficacy of extended metacognitive training for psychosis: A randomized controlled trial, Schizophrenia Research, https://doi.org/10.1016/j.schres.2019.08.006

R. Ishikawa et al. / Schizophrenia Research xxx (xxxx) xxx

4.3. General functioning We tested whether MCT improved social functioning and showed that participants in the TAU + MCT group improved their GAF compared to TAU. The improvement of GAF was may be influenced by the improvement of positive symptoms. Furthermore, group activity in the MCT would lead to the activation of participants' social functions. Thus, MCT appears to improve patients' general functioning, as was reported by Naughton et al. (2012), who found that the GAF score improved in patients who attended the MCT. However, other studies have not demonstrated the efficacy of MCT for social functioning. Briki et al. (2014) used a QOL scale, and Gawęda et al. (2015) used GAF to assess social functioning. Both studied found that MCT had no significant impact on patients' social functioning. Nonetheless, given the inconsistent results, further research is needed to clarify its effect on general functioning. 4.4. Cognitive insight Participants in the TAU + MCT group did not show improved BCIS scores after MCT. Our result was inconsistent with previous RCTs (Lam et al., 2015; Ochoa et al., 2017) that showed that MCT could improve cognitive insight; however, our methods differed from those employed in these previous studies. MCT modules were administered twice weekly in Lam et al. (2015), while our MCT modules were administered once weekly. Further, Ochoa et al. (2017) examined individuals with recent-onset psychosis, which differed from our sample (mean disease duration in years = 19.58 in the TAU + MCT group). These differences could affect the results. To improve cognitive insight, all modules may need to be administered twice a week. Further, MCT may be more effective in improving cognitive insight in patients with recent psychoses. 4.5. Other outcomes Within-participant comparisons in the TAU + MCT condition showed a marginally significant decrease baseline–post on BDI-II. Although causal conclusions cannot be drawn, our results suggest the possibility that MCT improve depressive symptoms. Because almost MCT modules typically target cognitive biases, only a few modules focused on depressive mood (e.g., module 8 include the themes “mood”) and self-esteem (e.g., additional two modules). More modules or repetition may be needed to significantly address these two broad domains. In addition, as depressive symptoms mediate the relationship between certain dysfunctional metacognitive beliefs and delusions (Gerlinger et al., 2013), interventions that improve both cognitive biases and depression may be effective for treating delusions. Research is needed to clarify how MCT can improve depression, and the relationships between depression, metacognitive biases, and delusions. Our assessments of self-esteem and health-related QOL were nonsignificant. However, changes in self-reported health outcomes and belief (e.g., self-concept) require time. If MCT improves patients' symptoms, they will be less worried by their symptoms and reduce their social avoidance, promoting their social activity. As patients' selfesteem would be fostered through this process, a long follow-up is necessary. This consideration is similar to Briki et al. (2014), who discussed the effects of MCT on social functioning. Future studies with larger samples and extended follow-ups are required to evaluate the stability of the treatment effects.

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follow-up period (one month); however, a 3- or 6-month follow-up period would better test the efficacy. Second, the TAU condition included voluntary attendance and a supportive therapeutic program, which included psychoeducation, computer training, and social activities. We did not control for these effects. Third, an a priori power analysis showed that N210 participants were needed for the primary analysis; however, the research collaborators at the psychiatric hospitals assumed that it would be difficult to recruit N50 patients who met inclusion criteria. Consequently, we aimed to recruit 50 eligible participants. However, a post-hoc power analysis showed that our sample size had adequate statistical power for our primary analysis (ANCOVA). Fourth, patients who missed more than three sessions (i.e., noncompleters) could no longer participate. Therefore, non-completers were not contacted for post and follow-up assessments. However, a stronger design would have been to collect assessment data from all participants, regardless of their attendance. Fifth, we did not use a measure that was specific to delusions and auditory hallucinations, such as the Psychotic Symptom Rating Scales (PSYRATS; Haddock et al., 1999). PSYRATS is not commonly used in Japan and was not available for this study. Consequently, we used PANSS scores as our primary outcome, which was completed by a trained examiner. Sixth, we did not use behavioral cognitive bias tasks (e.g., the beads task to assess JTC bias). Our RCTs were conducted in a daily clinical setting. As behavioral tasks take time, we were concerned that the patients might be burdened, so we did not use it and used a questionnaire scale as our outcome. Seventh, we restricted our inclusion criteria to an age range that was somewhat limited. Previous studies have restricted participants to under age 65 (e.g., Moritz et al., 2013; Briki et al., 2014; Favrod et al., 2014) with one (Lam et al., 2015) restricting participants to under 60. We restricted participants to those under age 60 to control for the potential of organic brain disorders, which may limit our findings, as our age range was not with those of previous studies. Eighth, since we used only the PANSS positive symptom subscale, we could not compare the ratio of clinically significant improvement on the PANSS. Ninth, based on previous studies (Gawęda et al., 2015; Lam et al., 2015), we used cognitive biases and insight variables as outcomes; however, cognitive biases could mediate changes in positive symptoms. Our study could not examine this relationship, which should be clarified in future research on cognitive biases and insight, as well as self-esteem and depressive mood, mediate changes in positive symptoms. Lastly, there may be differences between symptoms and subjective self-experience variables. MCT aims to reduce the prevalence of psychotic symptoms. Other metacognition reflection and insight therapy (MERIT) focuses on self-experience and is based on the integrative model of insight, which conceptualizes poor insight as being the result of a failure to create a coherent account of the complex events and personal experiences related to a psychiatric illness (Van Donkersgoed et al., 2014; Lysaker and Klion, 2017). MERIT outcomes are assessed using the Metacognitive Assessment Scale–Short Version (Lysaker and Klion, 2017). The theoretical and methodological differences between MERIT and MCT and outcome differences should be studied in the future.

5. Conclusion 4.6. Limitations and future directions Some limitations need to be acknowledged. First, the follow-up interval was short. To test the efficacy of the MCT, we restricted participants from receiving CBTp before the end of the follow-up period. The longer the follow-up period, the more it will restrict patients from accessing CBTp. To minimize this restriction, we utilized a short

This RCT tested the efficacy of a new 10-module MCT and provided substantial support regarding the efficacy of MCT on positive symptomatology. We demonstrated that MCT could improve patients' general functioning. There is also a trend of its efficacy on cognitive biases; however, its sustained long-term effects require further investigation.

Please cite this article as: R. Ishikawa, T. Ishigaki, T. Shimada, et al., The efficacy of extended metacognitive training for psychosis: A randomized controlled trial, Schizophrenia Research, https://doi.org/10.1016/j.schres.2019.08.006

8

R. Ishikawa et al. / Schizophrenia Research xxx (xxxx) xxx

Authors' contributions RI and TI designed the study and wrote the protocol. TS, HT, NY, NO, TM, and T Matsumoto recruited the patients. RI, TI, and MH managed the manuscript preparation. RI wrote the first draft of the manuscript. All authors contributed to and approved the final version of the manuscript. Funding This research was supported by Grant-in-Aid for Scientific Research (15H03455) from the Japan Society for the Promotion of Science (JSPS). Declaration of competing interest None. Acknowledgements The authors would like to thank all the participants for their time and participation in this project, as well as the medical staffs at Taniguchi Hospital (Ayaka Kodama, Kana Miyamoto, Shinya Kodama, Masami Meiri, Noriko Kobae, Kenji Hayashi, Reika Oshikawa, Naotaka Fujiwara), Wakakusa Hospital (Yasuyuki Sakurai, Takako Seo, Yakiko Tomimori), Sapporo Hanazono Hospital (Shouichi Tamamura, Shizuka Ebata, Taku Hashimoto, Mari Sugawara, Kanako Hagiwara), and Oouchi Hospital (Sachina Komikado, Kenji Maemura).

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Please cite this article as: R. Ishikawa, T. Ishigaki, T. Shimada, et al., The efficacy of extended metacognitive training for psychosis: A randomized controlled trial, Schizophrenia Research, https://doi.org/10.1016/j.schres.2019.08.006