TITLE: Randomized controlled trial on adjunctive cognitive remediation therapy for chronically hospitalized patients with schizophrenia

  ABSTRACT.BACKGROUND:
Cognitive remediation therapy (CRT) is one of the promising new non-drug approaches to reducing cognitive deficits of patients with schizophrenia that has not yet been fully evaluated in China.

ABSTRACT.AIM:
Assess the efficacy of CRT in improving the cognitive functioning, social functioning and insight of patients with chronic schizophrenia.

ABSTRACT.METHODS:
126 clinically stable inpatients with chronic schizophrenia were randomly allocated to an intervention group (with CRT) and a treatment as usual group (TAU) (which used standard occupational and recreational therapy methods). The treatment frequency and duration were the same for the two groups: five times per week for three months. The Wisconsin Card Sorting Test (WCST) was used to evaluate before versus after changes in cognitive function, the Scale of Social Skills of chronic schizophrenia Inpatients (SSSI) was used to assess social functioning, and the Insight and Treatment Attitude Questionnaire (ITAQ) was use to assess insight.

ABSTRACT.RESULTS:
Four patients dropped out during the study leaving 60 in the CRT group and 62 in the TAU group in the final analysis. Both groups showed significant improvement in WCST measures over the three-month trial but the improvement in the CRT group was significantly greater than that for the TAU group on all of the WCST measures assessed. The total SSSI score improved significantly in both groups over the three months, but the improvement in the two groups was not significantly different. The total ITAQ score also showed significant improvement in both groups over the three months and the degree of improvement was significantly greater in the CRT group than in the TAU group.

ABSTRACT.CONCLUSION:
As an adjunctive treatment to antipsychotic medication, a three month course of CRT is more effective at improving the cognitive functioning and insight of hospitalized patients with chronic schizophrenia than routine occupational and recreational therapy.

BODY.INTRODUCTION:
1.  Schizophrenia is a severe mental illness with unknown etiology, poor prognosis and a high disability rate. There are no proven preventive measures[1],[2] but several medications can treat the clinical symptoms of the disorder. Deficits in cognition, social functioning and insight into the illness often occur but there are few effective interventions for dealing with these components of the illness. In an attempt to simultaneously address the clinical symptoms and the cognitive and social deficits, newer therapeutic approaches to schizophrenia have combined psychopharmacology and different types of cognitive therapies. Cognitive remediation therapy (CRT) is one of the promising new non-drug therapies[2] that specifically focuses on the cognitive deficits commonly seen in schizophrenia. The current study assesses the efficacy of the CRT paradigm[3],[4] developed by Ann Delahunly and Rodney Morice in the treatment of the cognitive deficits, social dysfunction and lack of insight of patients with chronic schizophrenia in China.

BODY.SUBJECTS AND METHODS:
2.

BODY.SUBJECTS AND METHODS.SUBJECTS:
2.1  The enrollment of patients is shown in Figure 1. Patients admitted to the Third People's Hospital of Lanzhou Municipality from March to December 2010 for acute relapses were screened for participation in the study after they completed 2-4 weeks of treatment for their acute symptoms. Individuals eligible for participation in the study met diagnostic criteria for schizophrenia (based on the third edition of the Chinese Classification and Diagnostic Criteria of Mental Disorders[5]), had a duration of illness of at least five years, were clinically stable at the time of enrollment (i.e., total score of Positive and Negative Syndrome Scale[6] [PANSS] <60 or a drop in the total PANSS score of more than 50% after initial treatment of acute symptoms), were 18-65 years of age, and were receiving maintenance treatment with a combination of clozapine and risperidone (the most common combined treatment regimen for chronic patients in our setting). Excluded patients included those with co-morbid mental retardation, perceptual disorders, organic brain disease, serious medical disorders, impulse control problems, or severe depressive or anxiety symptoms, and those who were pregnant or lactating. All participating patients and their guardians signed informed consent for the study.  The 126 eligible patients were randomly assigned to a CRT group or to a treatment as usual (TAU) group. The 63 patients in the CRT group included 40 men and 23 women with a mean (sd) age of 37 (8) years who had a mean duration of formal schooling of 11 (5) years, and a mean duration of illness of 23 (9) years. At the time of enrollment in the study their mean total PANSS score was 45.3 (13.1) and they were all receiving combined treatment with clozapine (mean dose of 278 [121] mg/d) and risperidone (mean dose of 3.4 [1.4] mg/d).  The 63 patients in the TAU group included 37 men and 26 women with a mean age of 38 (9) years who had a mean duration of formal schooling of 10 (4) years and a mean duration of illness of 24 (8) years. At the time of enrollment in the study their mean total PANSS score was 46.2 (13.6) and they were all receiving combined treatment with clozapine (mean dose of 285[126] mg/d) and risperidone (mean dose of 3.9[1.2] mg/d).  None of the subjects changed the dosage of antipsychotic medication over the three months of the study. There were no statistically significant differences in the gender, age, years of education, duration of illness, total PANSS score on enrollment, or dosage of medication between the two groups.

BODY.SUBJECTS AND METHODS.INTERVENTION:
2.2  The CRT employed in this study used a Chinese version of the CRT manual[3],[4] developed by Ann Delahunly and Rodney Morice. CRT is a comprehensive neuropsychological training method targeting various major cognitive deficits of schizophrenia that combines verbal reinforcement, errorless learning, individualized guidance and other cognitive therapeutic techniques. The cognitive functioning of patients in three primary areas—cognitive flexibility, working memory and planning—is improved as they complete cognitive tasks of increasing difficulty under the guidance of four trained therapists.[7]–[10] Training sessions lasted for 45 minutes each and were repeated five days a week for three months.  Figure 1.Flowchart for the study  The TAU group received routine occupational and recreational therapy and general mental health education including instructor-led music therapy, dance therapy and physical exercises as well as psychological counseling during daily ward rounds. This treatment also lasted 45 minutes per day and was provided five days per week for three months. The four therapists who provided CRT were different from the clinicians who provided TAU.

BODY.SUBJECTS AND METHODS.INSTRUMENTS:
2.3  The Wisconsin Card Sorting Test[11] (WCST) was used to evaluate before versus after changes in cognitive function, the Scale of Social Skills of chronic schizophrenia Inpatients[12] (SSSI) was used to assess social functioning, and the Insight and Treatment Attitude Questionnaire[13] (ITAQ) was used to assess insight. Five outcome measures were assessed for the WCST: total number of completed cards; number of cards correctly categorized, number of perseverative errors, number of random errors, and number of categories completed. SSSI is an interviewer-rated questionnaire developed in China specifically for chronic psychiatric inpatients with 10 items (scored on 0-2 point Likert scales) that have good internal consistency (alpha=0.89), test-retest reliability (rs=0.97), and inter-rater reliability (rs=0.98);[12] the total score (range 0-20) is used in the current study, with lower scores representing better functioning. The ITAQ is an interviewer-rated scale with 11 items (scored on 0-2 point scales) that have good internal consistency (alpha=0.91),[14] test-retest reliability (r=0.87),[14] and inter-rater reliability (Kappa=0.86);[15] the total score (range 0-22) is used in this analysis, with higher scores representing better insight. Two psychologists were trained to administer these instruments; their inter-rater reliability for the three instruments was assessed by comparing their results for 15 patients (ICC for WCST=0.80, ICC for SSSI=0.87, and ICC for ITAQ=0.92). These psychologists were not blind to the treatment status of the patients they evaluated.

BODY.SUBJECTS AND METHODS.STATISTICAL ANALYSIS:
2.4  All data were analyzed using SPSS 17 statistical software. Paired t-tests were used to compare before versus after results within groups, independent-sample t-tests were used to compare baseline scores in the two groups and F-tests were used to compare differences in the magnitude of the changes between the two groups over the three-months of treatment (adjusting for baseline values).  The study was approved by the Institutional Review Board of the Third People's Hospital of Lanzhou Municipality.

BODY.RESULTS:
3.  During the 3-month course of the study three patients dropped out of the CRT group (two were discharged and one withdrew consent) and one patient who was discharged dropped out from the TAU group. As shown in Table 1 the CRT group had significant improvements in all five measures derived from the WCST over the three-month trial but TAU only showed significant improvement in one of the five measures (total number of completed cards). The improvements in these WCST measures in the CRT group were significantly greater than those in the TAU group.   Table 1. Mean (sd) scores for different WCST measures before treatment and after three months of treatment in the two groups Group Total number of completed cards Number of cards correctly categorized Number of perseverative errors Number of random errors Number of categories completed CRT Group  Pre-treatment (n=63) 86.6 (11.5) 22.3(2.4) 29.2 (2.5) 37.2 (4.6) 2.5 (0.8)  Post-treatment (n=60) 73.0 (12.2) 25.8 (4.5) 25.0 (4.0) 30.7 (6.3) 3.5 (1.1)    paired t-test (p-value) 6.49 (<0.001) -5.29 (<0.001) 7.02 (<0.001) 6.10 (<0.001) -5.47 (<0.001) TAU Group  Pre-treatment (n=63) 84.7 (13.2) 21.6(2.6) 28.4 (2.3) 38.2 (6.9) 2.7 (1.0)  Post-treatment (n=62) 79.3 (11.5) 22.5 (2.6) 27.5 (3.2) 36.0 (5.9) 3.0 (1.2)    paired t-test (p-value) 2.43 (0.018) -1.95 (0.056) 1.84 (0.071) 1.97 (0.054) -1.29 (0.201) CRT vs. TAU  Pre-treatment 0.88 (0.381) 1.51 (0.134) 1.83 (0.070) 0.98 (0.382) 1.20 (0.231)    t-test (p-value)  Post-treatment 8.46 (0.004) 24.54 (<0.001) 15.29 (<0.001) 22.62 (<0.001) 5.62 (0.019)    F-test a  (p-value) WCST, Wisconsin Card Sorting Test; CRT, cognitive remediation therapy; TAU, treatment as usual a F-test compares post-treatment results controlling for pre-treatment values   As shown in Table 2, the ITAQ total score improved significantly in both groups over the treatment period and the improvement in the CRT group was significantly greater than that in the TAU group. The SSSI total score also improved significantly over the three months in both groups; the magnitude of improvement in the SSSI total score was greater in the CRT group than in the TAU group but this difference did not reach statistical significance (p=0.074).  Table 2. Mean (sd) SSSI and ITAQ total scores before treatment and after three months of treatment in the two groups Group SSSI score ITAQ score CRT Group  Pre-treatment (n=63) 20.2 (1.5) 6.6 (1.9)  Post-treatment (n=60) 13. 6 (2.1) 9.3 (1.1)    paired t-test (p-value) 20.25 (<0.001) -9.07 (<0.001) TAU Group  Pre-treatment (n=63) 19.8 (1.2) 7.1 (1.7)  Post-treatment (n=62) 14.2 (1.8) 8.5 (1.1)    paired t-test (p-value) 21.66 (<0.001) -5.46 (<0.001) CRT vs. TAU  Pre-treatment 1.82 (0.071) 1.72 (0.088)    t-test (p-value)  Post-treatment 3.33 (0.074) 13.38 (<0.001)    F-test a  (p-value) SSSI, Scale of Social Skills of chronic schizophrenia Inpatients ITAQ= Insight and Treatment Attitude Questionnaire CRT, cognitive remediation therapy TAU, treatment as usual a F-test compares post-treatment results controlling for pre-treatment values 

BODY.DISCUSSION:
4.

BODY.DISCUSSION.MAIN FINDINGS:
4.1  Similar to studies in other countries,[16] we found that adjunctive treatments focused on cognitive functioning, social functioning and insight for inpatients with chronic schizophrenia can significantly improve objective measures of their functioning. Three months of non-specific standard occupational and recreational therapy combined with routine mental health education sessions ('treatment as usual') also had significant beneficial effects on social functioning and insight but had limited effects on cognitive functioning. The manualized cognitive remediation therapy intervention employed in this study resulted in a significantly greater improvement in executive functioning and in insight than was seen with TAU.  Both treatment groups had significant improvements in social functioning over the three months of treatment but the improvement in the CRT group, though larger than in the TAU group, was not significantly better than that in the TAU group. One possible reason for the lack of significant group differences with the SSSI is the difficulty of assessing social functioning in schizophrenia,[17],[18] particularly in inpatient settings where the range of social skills that can be assessed is quite limited.  Several important questions remain to be answered by subsequent studies. Are the greater improvements seen with CRT persistent over time or would prolongation of the treatments beyond three months result in a decrease (or increase) in the differential outcomes for TAU and CRT? How long are the improvements sustained after a course of treatment: do patients need to have continuous CRT or 'booster sessions' of CRT to sustain their improvements in cognition, social functioning and insight? And do outpatients with schizophrenia experience similar improvements with CRT to those seen in these inpatients?

BODY.DISCUSSION.LIMITATIONS:
4.2  Several limitations need to be considered when evaluating these results. The evaluation of outcomes was not done blindly so it is difficult to be certain that there was no bias in the evaluations. The WCST only assesses one component of cognitive functioning (executive functioning) so other measures would need to be used to more comprehensively assess cognitive functioning. All patients involved in the study were inpatients with chronic schizophrenia, so the improvement in cognitive functioning and insight found may not be relevant for outpatients or for patients with a relatively short duration of illness.

BODY.DISCUSSION.SIGNIFICANCE:
4.3  This randomized controlled trial provides clear evidence of the benefits of a three-month course of CRT as an adjunctive treatment for patients with chronic schizophrenia who have been hospitalized following an acute relapse of illness. Further study is needed to determine whether or not CRT should be continuously or intermittently provided to hospitalized patients. Other studies with outpatients are needed to determine whether or not the benefits identified with Chinese inpatients with schizophrenia would also be seen in community-based patients.

Question: Compared to Treatment as usual what was the result of Cognitive remediation therapy on Improvement in the Wisconsin Card Sorting Test?
Evidence: The total ITAQ score also showed significant improvement in both groups over the three months and the degree of improvement was significantly greater in the CRT group than in the TAU group.
Answer: significantly increased