Metacognitive Training and Insight in Schizophrenia
Metacognitive Training and Insight in Schizophrenia
Although insight in schizophrenia spectrum disorders (SSD) has been associated with positive
 outcomes, the effect size of previous treatments on insight has been relatively small to
 date. The metacognitive basis of insight suggests that metacognitive training (MCT) may
 improve insight and clinical outcomes in SSD, although this remains to be established.

 This single-center, assessor-blind, parallel-group, randomised clinical trial (RCT) aims to
 investigate the efficacy of MCT for improving insight (primary outcome), including clinical
 and cognitive insight, which will be measured by the Schedule for Assessment of Insight
 (Expanded version) (SAI-E) and the Beck Cognitive Insight Scale (BCIS), respectively, in (at
 least) n=126 outpatients with SSD at three points in time: i) at baseline (Time 0); ii) after
 treatment (Time 1) and iii) at 1-year follow-up (Time 2). SSD patients receiving MCT and
 controls attending a non-intervention support group will be compared on insight level changes
 and several clinical and cognitive secondary outcomes after treatment and at follow-up,
 whilst adjusting for baseline data. Ecological momentary assessment (EMA) will be piloted to
 assess functioning in a subsample of participants.

 This will be the first RCT testing the effect of group MCT on multiple insight dimensions (as
 primary outcome) in a sample of unselected patients with SSD, including several secondary
 clinically relevant outcomes, namely symptom severity, functioning, which will also be
 evaluated with EMA, hospitalizations and suicidal behaviour.
INTRODUCTION:

 Schizophrenia and related disorders remain associated with relatively poor psychosocial
 outcomes. Impaired insight has been reported to be the strongest predictor of this poor
 outcome in psychotic disorders. However, the effect size of previous treatments on insight
 changes in psychotic disorders has been relatively small to date, which may have been the
 result of not tackling the actual underpinnings of insight in psychosis.

 Several theories have been proposed to explain what underlies 'lack of insight' in
 schizophrenia spectrum disorders. First, lack of insight could be viewed as having a function
 in terms of being protective or preserving self-esteem, i.e., a denial mechanism. Second,
 lack of insight may also be considered as a primary symptom of the disorder. Third, the
 neurocognitive basis of insight was in part supported by a meta-analysis, which also
 suggested that other variables, namely metacognition, which was defined as 'the ability to
 think of one's and others' thinking', may affect insight. Indeed, patients with schizophrenia
 have been reported to show metacognitive deficits and poorer metacognitive performance is
 linked with impaired insight in schizophrenia. Metacognitive training (MCT) may therefore
 improve insight, which should also have a positive impact on clinical outcomes, although no
 previous randomized clinical trials (RCT) have investigated this.

 MCT was first developed by Steffen Moritz and Todd Woodward and is available at no cost at:
 http://www.uke.de./mct. Since then, one systematic review and four meta-analyses have
 replicated the positive effects of MCT on positive symptoms, particularly delusions, when
 compared with 'treatment as usual' (TAU), although one meta-analysis failed to show such an
 association. However, to the best of our knowledge no definitive randomised clinical trial
 (RCT) using MCT has considered insight as primary outcome to date, although three previous
 RCTs found other non-MCT metacognitively oriented therapies to improve insight in
 first-episode psychosis and schizophrenia.

 Clinical and cognitive insight are different, albeit related, concepts. There has been a
 growing interest in clinical insight in psychosis since the multidimensional model of insight
 proposed by David, which encompasses three different, albeit overlapping, dimensions -
 illness recognition, symptom relabelling and treatment compliance - and has been consistently
 replicated ever since. Multidimensional measurement scales, such as the Scale of Uawareness
 of Mental Disorder (SUMD) and the Schedule for Assessment of Insight (SAI-E), were also
 devised for research. Cognitive insight is a core metacognitive domain which refers to the
 person's ability to evaluate and correct his/her own distorted beliefs and misinterpretations
 (self-reflectiveness) and the tendency to overconfidence in one's conclusions
 (self-certainty).

 The main aim of this RCT is to test whether MCT can improve insight, including clinical and
 cognitive insight, in patients with schizophrenia over a 1-year follow-up. As secondary aims,
 the effect of MCT-related insight changes on clinical outcomes, including symptomatic
 severity, hospitalizations, suicidal behaviour and psychosocial Functioning, will be
 investigated. In addition, the investigators will pilot the use of ecological momentary
 assessment (EMA) via two web-based applications - www.MEmind.net and the Evidence-Based
 Behaviour platform eB2 app - to measure functioning in a subsample of participants.

 Specifically, the following five hypotheses are to be tested: i) that MCT will result in
 higher cognitive and clinical insight levels and that MCT-induced insight improvement will be
 linked with (compared with controls): ii) reduced symptom severity and iii) lower risk of
 hospitalizations, iv) lower suicide rates and v) better functioning.

 METHODS:

 Study design This is a single-center, assessor-blind, parallel group, two-armed randomised
 controlled trial (RCT) over a 1-year follow-up period. Participants will be assessed at
 baseline, following which they will be randomised to either group MCT (experimental group) or
 a support group (control group) and they will be reassessed after treatment, i.e., at
 approximately 8 weeks, and at 1-year follow-up.

 The study protocol has been approved by the local Research Ethics Committee of the Instituto
 de Investigación Sanitaria (IIS)-Fundación Jiménez Díaz (Madrid, Spain), from which patients
 will be recruited as detailed below, and registered as RCT-EC044-19_FJD_HRJC.

 Recruitment process:

 Recruitment will occur at the outpatient clinic known as Centro de Salud Mental de
 Arganzuela, which is part of Instituto Fundacion Jimenez Diaz, that is, the 'sponsor', at
 which two consultant psychiatrists and one consultant psychologist will refer potential
 candidates to the principal investigator of the project (JDLM) to arrange a first
 pre-recruitment interview during which the relevant information of the project is explained
 to the candidate in lay terms, including an information leaflet. Those agreeing to
 participate in the study are screened against the above inclusion/exclusion criteria at this
 point. Those who are found to fulfill the study selection criteria undertake a neurocognitive
 assessment. Specifically, the WAIS-IV is administered by a MSc-level clinical psychologist in
 order to rule out an IQ≤70, which is an exclusion criterion. Those with an IQ>70 are
 administered the Trail Making Test (TMT), which assesses executive function and has been
 found to correlate with insight scores in psychosis patients, shortly after the WAIS-IV in
 order to complete the baseline neurocognitive assessment at this point.

 After a short break of around 5 minutes, the 'assessor' (JDLM) performs the MINI
 International Psychiatric Interview to confirm the diagnosis of psychosis and conducts the
 psychopathological, insight, metacognitive and functioning assessments detailed below. Also,
 a set of demographic and clinical variables, which are listed below, are collected at this
 baseline interview.

 All participants will be encouraged to continue taking medication as prescribed by the
 treating consultant psychiatrist, usually antipsychotics, and to receive non-metacognitive
 oriented psychotherapy, such as psychoeducation. There will be no restrictions on medication
 changes over the trial, which can be made by the treating consultant at any time, although
 medication-related variables will be considered in secondary analyses as potential
 mediators/confounders. Participants are informed of their right to drop out of the study at
 any time without having to disclose a specific reason, which will have no implications on
 treatment or service provision. Participants are not compensated with any amount of money for
 completing the assessments and/or receiving the interventions, namely MCT or attending a
 weekly support group.

 Randomisation and assessor-blindness:

 After the baseline (Time 0) assessment participants are randomised to either MCT or the
 support group, both of which are run by two researchers, through a computerized plan (no
 stratification factors) in blocks of 10 subjects (maximum number of each group) and assessor
 (JDLM)-patient blind. Only one co-principal investigator of the project (EBG) has access to
 the randomisation plan, but the assessor (JDLM) is not informed of the patient's allocation
 group, thus ensuring assessor-blindness. Since the patient may find out what intervention
 he/she is receiving the study cannot be considered to be 'double-blind', although it is
 'single-blind', that is, 'assessor-blind'. Also, big efforts will be made on the ground to
 reduce the risk that the assessor (JDLM) may become accidentally unblinded and patients are
 reminded that they should not disclose their group assignment at any time. At the end of the
 baseline assessment, participants receive an envelope with the intervention assignment from
 an independent administrator who is not involved in the research team. A reminder mobile
 text-message is also sent to participants within the next 24 hours with the group details
 (date, time and venue), which is also re-sent again during the 24 hours prior to the
 appointment, which is very similar to our routine clinical practice. Hence,
 assessor-blindness is guaranteed at all times throughout the study period since the assessor
 (JDLM) is not involved in the randomization plan or the active interventions.

 Assessments:

 Participants will be assessed at three timepoints: i) at baseline (Time 0); ii) after
 treatment (Time 1); iii) at 1-year follow-up (Time 2). Data on different variables will be
 collected at each of these assessments.

 The assessor (JDLM) completed a rater-training workshop and received individual training in
 which they were observed as they assessed pilot patients by using the project scales
 explained below under the supervision of a senior consultant psychiatrist with expertise in
 the use of these instruments (EBG).

 Additional variables:

 Demographic and clinical data:

 At baseline data on the following demographic and clinical variables will be collected:
 gender, age at the study inception, nationality, ethnicity, marital status, education level,
 living status, employment status, ICD-10 diagnosis, duration of untreated psychosis, number
 of previous admissions, number, date and method of previous suicidal acts, current
 medications, alcohol/illicit drugs dependence (present/absent), medical comorbidities
 (present/absent) family history of mental illness (present/absent).

 Marital status, living status and employment status will be reassessed at 1-year follow-up as
 measures of functioning.

 Premorbid adjustment:

 Premorbid adjustment, which can be defined as 'the degree of achievement of developmental
 goals' will be retrospectively rated with the Premorbid Adjustment Scale (PAS). Specifically,
 the PAS provides scores on the level of adjustment over i) childhood (to age 11), ii) early
 adolescence (age 11-15), iii) late adolescence (age 15-17) and iv) adulthood (age ≥18). With
 regard to childhood and adolescence, items inquiry about sociability and social withdrawal,
 peer relationships, scholastic performance, adaptation to school and ability to form
 socio-sexual relationships. The questions regarding adulthood focus on social relationships
 by asking about educational achievement, social relationships and level of interest in, and
 enjoyment of, major life activities, such as work or family.

 Neurocognition:

 The neurocognitive assessment battery, which will be administered at the three assessments,
 will include the short version of the Wechsler Adult Intelligence Scale (WAIS) Revised, which
 estimates current intelligence quotient (IQ), and the Trail Making Test (TMT), which assesses
 executive function. Subtracting time in seconds to complete TMT task B minus time in seconds
 to complete TMT task A gives a measure of executive function, whilst controlling for
 processing speed.

 Metacognition:

 Three metacognitive tasks will be completed by participants at baseline, after treatment and
 at 1-year follow-up:

 -  Jumping to Conclusions (JTC) will be determined with the beads task. During this task,
 the individual is asked to decide the jar to which the extracted bead belongs on the
 basis of probability (in task 1 the probability is 85:15, while in task 2 the
 probability is 60:40). 'JTC' is considered as making a decision after extracting one or
 two beads.

 -  The Hinting Task will be used to measure Theory of Mind (ToM) performance. Learning is
 avoided by using different stories at the three assessments. Cronbach's α was good
 (0.64) for the Spanish version.

 -  In addition, the Emotional Recognition Test Faces, which is composed of 20 different
 pictures representing people's emotions, will be used to evaluate ToM.

 Statistical analysis:

 Participants' data will be analysed at the end of the study on an intention-to-treat (ITT)
 basis, thus including all patients with baseline information available. Imputation methods
 will be used to estimate missing values. All the analyses will be performed with the
 Statistical Package for Social Science version 25.0 (SPSS Inc., Chicago, IL, USA).

 First, demographic and clinical characteristics of groups (MCT and controls), including
 insight measures, will be compared at baseline so parametric and non-parametric tests will be
 used as appropriate. Also, for descriptive purposes, between-arm completion rates differences
 will be analysed at the end of the study.

 Second, in order to investigate the primary outcome of the study, namely insight changes over
 the trial period, univariate analysis of covariance (ANCOVA) models will examine
 between-group differences (MCT and controls) in the SAI-E and BCIS total and subtotal scores
 changes from Time 0 to Time 1 and from Time 0 to Time 2 (as the dependent variable), whilst
 adjusting for baseline data. Hence, the effects of treatment (independent of time) and
 treatment group allocation*time interactions on insight changes will be investigated. The
 investigators will also explore within-group scores changes between Time 0, Time 1 and Time
 2. Specifically, effect sizes (Cohen's d) and the corresponding 95% confidence intervals (CI)
 will be estimated from the imputed datasets for between- and within-group insight scores
 changes. In accordance with Cohen's conventions, effect sizes will be classified as 'small'
 (d<0.2), 'medium' (d=0.2-0.5) or 'large' (d>0.8). Due to multiple testing and the subsequent
 risk of type I error, results will be adjusted using Bonferroni correction.

 Third, for the secondary outcomes evaluated with continuous variables, i.e., symptom severity
 (PANSS and CDSS) and functioning (GAF, SDLS and WHODAS), analogous ANCOVA models will be
 used. For those binary secondary outcomes, namely suicidal behaviour and readmissions,
 survival analyses, i.e., multivariable Cox regression models, will model time to the outcome
 event (i.e., first suicidal event or hospital admission, respectively) or the censoring date
 as appropriate, whilst adjusting for baseline variables.

 Finally, variables inter-relationships over the trial period will be examined by means of
 path analysis through structural equation modeling, thus testing the effect of putative
 mediators/moderators/confounders/covariates, including neurocognition measures, on the above
 associations.

 Power calculations and estimation of sample size:

 Given that the mean SAI-E score for psychosis patients is 13/28 with a standard deviation of
 around 6, a difference of 2 points (e.g., 13 vs. 15) between groups (e.g., MCT vs. controls),
 which is considered to be clinically meaningful, is equivalent to an effect size of 0.33 with
 a two-tailed alpha significant level set at 5%. Under these assumptions, for reaching a
 sufficient statistical power of β=80% at the end of the study, n=63 subjects in each arm will
 be needed, that is, a total sample size of N=126 patients, who will be analysed at the end of
 the study on an intention-to-treat (ITT) basis. Attrition rates in previous RCTs
 investigating MCT effects on symptoms were low (approximately 10%). However, since
 participants will be followed-up over a more prolonged period (1 year) the investigators have
 conservatively assumed a much higher drop-out rate of 50%. Under this assumption, the study
 will be carried out with an initial sample size of N=252 patients, i.e., n=126 participants
 in each group/arm at the study inception, which will also allow both ITT and 'per protocol'
 analyses with sufficient power.
Inclusion Criteria:

 -  Age: 18-64 years, both inclusive

 -  Diagnosis: schizophrenia spectrum disorder (F20-F29, ICD-10)

 -  Outpatient status

 Exclusion Criteria:

 -  IQ≤70 as measured by the short form of the Wechsler Adults Intelligence Scale (WAIS)
 (Wechsler, 1981).

 -  History of head injury and/or a neurological condition.

 -  Having received a metacognitively oriented therapy within the previous 12 months.

 -  Low level of Spanish.

 -  Lack of cooperativeness with the assessment and/or "intervention".