Effect of Computer-Assisted Cognitive Remediation Therapy on Cognition among Patients with Schizophrenia: A Pilot Randomized Controlled Trial

In schizophrenia, cognition is closely linked to social competence and influences long-term prognosis. Thus, treatment should target cognitive improvement to enhance the patient’s societal adaptation. This study evaluated the effects of computer-assisted cognitive remediation therapy (CR) using RehaCom® on cognition in patients with schizophrenia. Thirty patients were randomized, with 15 assigned to the CR and treatment as usual (TAU) group and 15 to the TAU-alone group. Over 12 weeks, patients received CR twice weekly, including two computer sessions and one verbal session. The outcomes measured were cognition using the Brief Assessment of Cognition in Schizophrenia and Schizophrenia Cognition Rating Scale, intrinsic motivation using the Quality of Life Scale and Intrinsic Motivation Inventory, psychiatric symptoms using the Positive and Negative Syndrome Scale, negative symptoms using the Scale for the Assessment of Negative Symptoms, and functional level using the modified Global Assessment of Functioning scale for Functioning. The CR + TAU group demonstrated considerable improvements in cognition, intrinsic motivation, and functional level compared to the TAU-alone group. These findings indicate that the CR using RehaCom® enhances cognition and other outcomes in schizophrenia.

CR therapy methodologies vary and include bottom-up vs. top-down, computerbased vs. non-computer-based, group vs. individual, tailored vs. standardized, and combined vs. not combined with other treatments [14][15][16][17].A meta-analysis by Twamley et al. [18] showed that the effect size of computer-assisted CR therapy on cognition was greater than that of non-computer-assisted therapy.While the benefits of CR therapy are recognized, more information is required on effective CR therapy methodologies and related factors to formulate evidence-based recommendations for enhancing cognition in patients with schizophrenia.
We devised a CR therapy program utilizing the Japanese version of the Higher Brain Function Training System RehaCom ® "http://www.hasomed.de(accessed on 20 December Eligible participants were randomized into the CR + TAU and TAU-alone groups by independent study staff, with whom there was no patient contact, using a computergenerated randomization program.Randomization was stratified by sex (male/female) and age (20-29, 30-39, 40-49, 50-59, and 60-65 years).Within each stratum, participants were randomized 1:1 to TAU + AE or TAU alone.The treatments were open-label; however, the assessors were blinded to the treatment allocation.

Interventions 2.4.1. CR Therapy
The CR therapy included computer and verbal sessions.The modules of the computerassisted RehaCom ® -based CR therapy modules included 24 individual 60 min sessions, 2 sessions/week, over 12 weeks.CR therapy was conducted on a computer with a special input panel using the Japanese version of the RehaCom ® software package Ver.1.0(KISSEI COMTEC Co., Ltd., Matsumoto, Japan).RehaCom ® is a computer system for continuous cognitive training such as attention, memory, executive function, and visual perception.Each RehaCom ® module was classified according to the categories established by the MATRICS TM Consensus Cognitive Battery (MCCB TM ) [24,25]: speed of processing, attention/vigilance, working memory, verbal learning and memory, visual learning and memory, reasoning and problem-solving, and social cognition (see Appendix A, Table A1).The characteristics of RehaCom ® include a highly game-like training menu and a function that automatically adjusts the difficulty level according to the patient's performance so that patients always receive the appropriate stimulation and continue to work on the training modules with motivation.Occupational therapists certified as cognitive remediation specialists administered the CR therapy.Patients used a desktop computer and an ergonomic keyboard.Each training session was divided into modules selected by the therapists in various cognitive domains.Appendix B, Table A2 provides the details of the treatment schedule for CR therapy.Further details of the RehaCom ® software are described at http://www.hasomed.de(accessed on 20 December 2019).In addition to the computer sessions using RehaCom ® , one-on-one verbal sessions to bridge the gap between improvements in cognitive impairment and daily functioning [12,13,26] were conducted with the therapist.Bridging interventions aid patients in applying their cognition to their daily functioning and promote socialization.The topics in this intervention included community living, the role of cognition in social skills, and problem-solving concerning compensatory strategies for dealing with daily living challenges.CR therapy was considered complete when patients participated in a minimum of 80% of the 24 scheduled treatment sessions.

TAU
All patients received standard treatment throughout the study, including regular meetings with a psychiatrist, antipsychotic medication, individual case management, and rehabilitation programs such as occupational therapy, at the same frequency as the CR + TAU group.Patients in the TAU-alone group received the same number of hours and amount of TAU intervention as those in the TAU + CR group.

Feasibility and Acceptability Outcomes
The feasibility and acceptability outcomes were the number of eligible patients randomized among the referred and recruited patients, retention rate by the proportion of participants with outcome measures at post-intervention and data completion, acceptability of treatments by dropout from the allocated group, and treatment adherence rate by the proportion of participants receiving a threshold dose of the CR therapy intervention (80% or more) in the CR + TAU group.CR therapy implemented in >80% of the patients indicated good adherence to CR therapy protocols.

Efficacy Outcomes
Efficacy outcomes were collected at baseline and 12 weeks.The primary efficacy outcome was the change in cognition examined from the baseline to 12 weeks using the Brief Assessment of Cognition in Schizophrenia (BACS).The secondary efficacy outcomes included changes in intrinsic motivation, psychopathology, and functional levels from baseline to 12 weeks.
Cognition was examined with the BACS [27,28] and the Schizophrenia Cognition Rating Scale (SCoRS) [29][30][31].The BACS consists of six domains: verbal memory (list learning), working memory (digit sequencing task), motor speed (token motor task), verbal fluency (category instances and letter fluency), attention and processing speed (symbol coding), and executive function (Tower of London test).The Z-scores were created to standardize each of the six domains, wherein the mean of healthy controls was set to zero and the standard deviation was set to one.The composite score was calculated as the average Z-score for each of the six BACS measures.The SCoRS is a 20-item interviewbased measure of cognitive impairment with questions aimed at the degree to which this impairment impacts daily functioning.Additionally, a global rating, which reflects the overall impression of the level of cognitive difficulty of patients in 20 cognition areas, was generated.The items were developed to examine the cognitive domains of memory, learning, attention, working memory, problem-solving, motor skills, social cognition, and language production.Each item was rated on a scale ranging from 1 to 4, and the global rating ranged from 1 to 10, with higher ratings reflecting greater impairment.The anchor points for each item focused on the impairment degree in that ability and the degree to which the deficit impaired daily functioning.The evaluators only considered cognitive deficits and attempted to rule out non-cognitive sources of deficits.The complete SCoRS administration included three various ratings: ratings based on an interview with the patient, an interview with an informant (i.e., the person who had the most regular contact with the patient in everyday situations), and generated by the interviewer who administered the scale to the patient and informant.The SCoRS total is the sum of the 20 SCoRS items.
Intrinsic motivation was examined using the sum of the following three items from the Quality of Life Scale (QLS), sense of purpose, motivation, and curiosity [32][33][34], as well as by using the Intrinsic Motivation Inventory (IMI) [35].The QLS is rated on a scale ranging from 0 to 6, with higher scores indicating better functioning.The IMI is a 21-item self-reporting scale that measures interest/enjoyment, value/usefulness, and perceived choice.The items were answered on a 7-point Likert scale with responses ranging from "not at all true" to "very true" with a higher total score reflecting greater intrinsic motivation for a specified task.
Psychiatric symptoms were examined using the Positive and Negative Syndrome Scale (PANSS) [36], which is a 30-item rating scale designed to assess psychotic symptom severity and consisting of three domains: positive, negative, and general psychopathology.Each item is rated from 1 to 7, with higher scores indicating more severe symptoms.
Negative symptoms were assessed with the Scale for the Assessment of Negative Symptoms (SANS) [37], which consists of 30 items that result in global ratings in five symptom complexes: affective flattening, alogia, avolition/apathy, anhedonia/asociality, and attention.Each item and its global ratings range from 0 to 5, with higher scores indicating more severe negative symptoms.
The functional levels were examined using the modified Global Assessment of Functioning (mGAF-original) scale [38].Eguchi et al. [39] translated the original mGAF [38] into Japanese and developed the psychological symptom (mGAF-S) and social functioning (mGAF-F) subscales by splitting the items and anchor points of the original mGAF scale.We used the mGAF-F, a single-item rating scale, to measure the functioning of the patients.Scores on each scale are rated between 21 and 90, with higher scores indicating better functioning.

Statistical Analysis
We summarized the descriptive statistics for the feasibility outcomes.T-tests for continuous data and χ 2 tests for categorical data were used to determine the group differences in sociodemographic and clinical characteristics.We performed an analysis of covariance (ANCOVA) with an intention-to-treat analysis of each outcome measure using all available data to evaluate the efficacy outcomes.We conducted an ANCOVA with the post-intervention assessment score as the dependent variable and the baseline score, age, sex, baseline IMI total, and baseline QLS total as covariates to examine group differences in the primary efficacy outcome.Moreover, we examined group differences in secondary efficacy outcomes using ANCOVA, with post-intervention scores as the dependent variable and baseline scores, age, and sex as the covariates.Treatment effects were estimated at the 12-week point, with an interaction between group and time.The Bonferroni method was used for multiple comparisons.Furthermore, we calculated the effect sizes with ηp 2 for intervention changes.Statistical significance was set at p < 0.05 for a two-sided test.Statistical analyses were performed using SPSS Statistics version 28.0.(IBM, Armonk, NY, USA).

Participants
Figure 1 illustrates a flowchart of the study.Of the 34 patients enrolled in the trial, 30 met the inclusion criteria.Among the 30 patients who were randomized (mean age, 47.63 years [standard deviation (SD) = 9.44]; 19 [63%] males), 15 (53%) were in the CR + TAU group and 15 (73%) were in the TAU-alone group.Of these, 27 (63%), 14 (50%), and 13 (71%) in the CR + TAU, CR + TAU, and TAU-alone groups, respectively, completed the trial.The demographic characteristics were not significantly different between the groups (Table 1).Additionally, none of the groups exhibited considerable changes in medication use from baseline to 12 weeks.One patient in the CR + TAU and two in the TAU-alone groups dropped out.Reasons for dropping out of the study existed, including withdrawal of consent (n = 3).
years [standard deviation (SD) = 9.44]; 19 [63%] males), 15 (53%) were in the CR + TAU group and 15 (73%) were in the TAU-alone group.Of these, 27 (63%), 14 (50%), and 13 (71%) in the CR + TAU, CR + TAU, and TAU-alone groups, respectively, completed the trial.The demographic characteristics were not significantly different between the groups (Table 1).Additionally, none of the groups exhibited considerable changes in medication use from baseline to 12 weeks.One patient in the CR + TAU and two in the TAU-alone groups dropped out.Reasons for dropping out of the study existed, including withdrawal of consent (n = 3).Student's t-test for the continuous variables and χ 2 analyses for the categorical variables were used to compare the groups.CR, cognitive remediation; FGA, first-generation antipsychotics; SD, standard deviation; SGA, second-generation antipsychotics; TAU, treatment as usual.

Feasibility and Acceptability Outcomes
Overall, the results indicated retention rates of 90% and 93% in the CR + TAU and 87% in the TAU-alone groups, respectively.Furthermore, 14 patients (100%) in the CR + TAU group completed > 80% of the sessions.No accidents or injuries occurred during the CR therapy intervention.
The baseline assessment findings were comparable between the groups, indicating no significant differences.Table 2 and Figure 2 show the differences in the changes from baseline to 12 weeks between the groups.The differences in change from baseline to 12 weeks for working memory (F = 7.40, p = 0.04, ηp 2 = 0.14), verbal fluency (F = 10.85,p = 0.01, ηp 2 = 0.19), and composite score (F = 14.49, p < 0.00, ηp 2 = 0.24) were significant.

Secondary Efficacy Outcomes
The differences in the baseline assessment results were insignificant.Table 2 shows the differences between the groups in terms of the changes from baseline to 12 weeks.The differences between groups in terms of the changes from baseline to 12 weeks were significant for QLS score (F = 47.27,p < 0.00, ηp 2 = 0.50), SANS anhedonia/asociality (F = 10.66,p = 0.01, ηp 2 = 0.19), and mGAF-F score (F = 18.72, p < 0.00, ηp 2 = 0.29).

Secondary Efficacy Outcomes
The differences in the baseline assessment results were insignificant.Table 2 shows the differences between the groups in terms of the changes from baseline to 12 weeks.The differences between groups in terms of the changes from baseline to 12 weeks were significant for QLS score (F = 47.27,p < 0.00, ηp 2 = 0.50), SANS anhedonia/asociality (F = 10.66,p = 0.01, ηp 2 = 0.19), and mGAF-F score (F = 18.72, p < 0.00, ηp 2 = 0.29).

Main Findings
This study assessed the feasibility and effectiveness of incorporating RehaCom ® -based CR therapy into TAU on cognition and other outcomes in patients with schizophrenia at a Japanese psychiatric hospital.To the best of our knowledge, this is the first randomized trial to indicate that utilizing the Japanese version of RehaCom ® in CR therapy showed promising feasibility and efficacy in improving cognition in patients with schizophrenia.
This study offers encouraging evidence that adding RehaCom ® -based CR therapy to TAU is feasible and well-received, as evidenced by high patient adherence and retention rates.Patients in the CR + TAU group successfully completed the program without worsening medical conditions and no adverse events, indicating good acceptability and tolerance.These findings suggest the feasibility of employing RehaCom ® -based CR therapy in a Japanese psychiatric hospital.The ability to adjust difficulty levels based on the patient's performance, a feature installed in RehaCom ® , likely contributed to sustained motivation and engagement during CR therapy.
This study assessed the impact of adding RehaCom ® -based CR therapy to TAU on cognition in patients with schizophrenia, finding significant improvements in several cognitive domains in the CR + TAU group compared to the TAU-alone group.These results align with that of a previous study on CR therapy using RehaCom ® [19][20][21] and offer robust evidence for the efficacy of CR in enhancing cognition in schizophrenia.Although the TAU group also demonstrated a trend toward improved cognitive performance, the magnitude of these improvements in the CR + TAU group was greater than that in the TAU group.To improve outcomes, implementing CR therapy alone and CR with TAU may be crucial.As McGurk et al. and Wykes et al. [12,13] reported, combining CR with other rehabilitation programs often enhances cognitive improvement compared with CR alone.
A meta-analysis by Vita et al. [40] identified "active and trained therapists", "repeated practice of cognitive exercises", "structured development of cognitive strategies", and "facilitated transfer to everyday functioning" as core elements of cognitive improvement with CR.The combination of CR and TAU by RehaCom ® includes these four elements, and the results of this study demonstrate the importance of integrating CR and psychosocial rehabilitation.This may have had a synergistic impact on the findings of cognitive performance in the CR therapy program in this study.Targeting patients with schizophrenia may maximize cognitive benefits and improve functional outcomes.Further validation is required to assess the effects of CR-induced cognitive gains in patients with schizophrenia.
Several factors may explain the cognitive improvement found in this study.Compared to the TAU-alone group, the CR + TAU group demonstrated substantial improvement in cognition and intrinsic motivation [41][42][43], which are factors that enhance cognitive outcomes.Thus, improvements in intrinsic motivation might contribute to greater cognitive gains with CR therapy [17,41].However, the mechanisms through which RehaCom ®based CR therapy enhances cognitive performance in schizophrenia are not completely understood, necessitating further validation.
The primary goal of schizophrenia treatment involves improving functional outcomes [44][45][46].Notably, our results revealed that CR + TAU led to superior outcomes in improving the mGAF-F functional level compared to TAU alone.This can be attributed to significant improvements in cognition and intrinsic motivation.The combined benefits of CR therapy in these areas, alongside TAU, may enhance overall functional levels in patients with schizophrenia.The role of intrinsic motivation has been established [17,[41][42][43]47].Negative symptoms [44,48,49] are key elements of schizophrenia, affecting functional outcomes and mediating the link between cognition and functional outcomes.Proactive patients undergoing cumulative CR intervention can potentially improve cognition and intrinsic motivation, leading to better functional outcomes.The effects of CR interventions on negative symptoms should continue to be investigated.Furthermore, training for cognitive task sessions and verbal sessions for bridging improved cognition and real-world functioning is crucial in CR therapy [12,13,26].The results of this study revealed that the active participation of participants in CR resulted in improvements in cognition and intrinsic motivation.One-on-one verbal sessions with an occupational therapist and psychosocial treatments included in TAU may be effective in translating these improvements into real-world functioning.

Strengths and Limitations
This study's primary strength lies in the fact that we verified CR's feasibility and efficacy using RehaCom ® for patients with schizophrenia for the first time in Japan.These valuable insights into the methodology of CR with RehaCom ® can potentially guide clinicians in implementing an evidence-based intervention to improve cognition in patients with schizophrenia.
However, this study has several limitations.Firstly, the study results were limited by a small sample size and were conducted at a single site; therefore, our findings should be considered preliminary until replicated by future studies.Secondly, the inclusion criteria may restrict the applicability of the findings to broader populations.Thirdly, since the study participants comprised inpatients and outpatients, caution is advised in interpreting functional-level assessments.Fourthly, the study did not explore the optimal dose (duration, intensity, and frequency) to maximize cognitive performance and other outcomes, necessitating further investigation.Fifthly, significant cognitive improvements observed for patients receiving CR + TAU may be the cumulative effects of computer sessions in addition to verbal sessions, not computer sessions alone; however, the design of this study did not examine the separate impacts of computer and verbal sessions on the cognition of patients in the CR + TAU group.In addition, the TAU intervention received may have varied among patients, as the TAU content was not controlled.Finally, the absence of follow-up assessments to gauge lasting effects is a limitation.Additional follow-up studies are required to determine the impact of CR interventions on cognition.
Furthermore, it has recently been reported that non-invasive brain stimulation (NIBS), such as transcranial direct current stimulation to frontal lobe regions [50,51] or the combination of NIBS and CR, may further improve cognitive function in schizophrenia [52,53].Future studies should therefore examine the effects of adding NIBS to RehaCom ® -based CR therapy on improving cognitive dysfunction.

Conclusions
This study demonstrates that integrating CR therapy into standard care effectively enhances cognition in patients with schizophrenia.Combining RehaCom ® -based CR therapy with other psychosocial treatments may further elevate functional levels.These results advocate for the inclusion of this approach in schizophrenia treatment protocols.Additional research is needed to determine the prognostic significance of CR therapy.

Figure 2 .
Figure 2. Change in BACS subtests and composite scores from the baseline to 12 weeks.The F−value in each panel is the test for the F−statistic of the interaction between time and treatment groups.Error bars indicate the standard error.BACS, Brief Assessment of Cognition in Schizophrenia; CR, cognitive remediation; TAU, treatment as usual.

Figure 2 .
Figure 2. Change in BACS subtests and composite scores from the baseline to 12 weeks.The F−value in each panel is the test for the F−statistic of the interaction between time and treatment groups.Error bars indicate the standard error.BACS, Brief Assessment of Cognition in Schizophrenia; CR, cognitive remediation; TAU, treatment as usual.
CR + TAU (n = 14)TAU Alone (n = 13) t/χ 2 p Age (years), mean (SD)Student's t-test for the continuous variables and χ 2 analyses for the categorical variables were used to compare the groups.CR, cognitive remediation; FGA, first-generation antipsychotics; SD, standard deviation; SGA, second-generation antipsychotics; TAU, treatment as usual.

Table 2 .
Change in the BACS subtests and composite scores from the baseline to 12 weeks.
** p < 0.01, * p < 0.05.BACS, Brief Assessment of Cognition in Schizophrenia; CR, cognitive remediation; mGAF-F, modified Global Assessment of Functioning social functioning subscale; PANSS, Positive and Negative Syndrome Scale; QLS, Quality of Life Scale; SANS, Scale for the Assessment of Negative Symptoms; SCoRS, Schizophrenia Cognition Rating Scale; SD, standard deviation; TAU, treatment as usual.Estimated effect size (

Table A2 .
Details of the treatment schedule for cognitive remediation therapy using RehaCom ® .