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Keywords:

  • antipsychotic medication;
  • neurocognitive rehabilitation;
  • schizophrenia;
  • synergistic effect

Abstract

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. References

Aim

Methods to improve neurocognitive impairments are of important research interest. This study sought to examine the synergistic effects of neurocognitive rehabilitation and antipsychotics for schizophrenia.

Methods

Subjects were 43 patients diagnosed with schizophrenia or schizoaffective disorder in a randomized trial of the effects of neurocognitive rehabilitation or a quasi-randomized experimental trial of supported employment with neurocognitive rehabilitation. We compared the effects of risperidone and aripiprazole in neurocognitive rehabilitation for schizophrenia. Subjects were divided into the following groups: (i) the control-risperidone group (CR group) (n = 13); (ii) the rehabilitation-risperidone group (RR group) (n = 9); (iii) the control-aripiprazole group (CA group) (n = 10); and (iv) the rehabilitation-aripiprazole group (RA group) (n = 11). Subjects in the rehabilitation group were engaged in computer-based cognitive exercises (24 sessions) with bridging group (12 sessions) over 12 weeks. Psychiatric symptoms, neurocognitive functioning and social functioning assessments were evaluated at baseline and at 12 weeks.

Results

A two-way anova with neurocognitive rehabilitation and antipsychotic medication as factors revealed a significant interaction effect on motor speed. Working memory and motor speed significantly improved in the RA group compared with the CA group. We found no significant improvements between the CR group and the RR group.

Conclusion

A synergistic effect of neurocognitive rehabilitation and aripiprazole was observed as improvement of motor speed. In patients treated with aripiprazole, neurocognitive rehabilitation appeared to improve working memory and motor speed. Further studies of synergistic effects of neurocognitive rehabilitation and antipsychotic medication are necessary to verify these findings.

Neurocognitive deficits in schizophrenia are among the strongest predictors of social outcomes as well as key functional outcome domains, such as the ability to develop social skills and function independently in the community.[1, 2] Therefore, methods to improve neurocognitive impairments through pharmacological treatment and cognitive remediation are of important research interest.[3]

It was generally thought that atypical antipsychotics would improve neurocognitive functioning. But some published reports suggest that the magnitude of neurocognitive functioning for antipsychotics is lower than previously expected. For example, in a double-blind study, antipsychotics, such as olanzapine, quetiapine, and risperidone, produced modest improvement in neurocognitive functioning.[4] In 20 clinical trials for cognitive enhancement, atypical antipsychotic medications moderately improved some aspects of cognitive functioning in patients with schizophrenia.[5]

Next, the influence of neurocognitive rehabilitation on neurocognitive functioning came to attract attention. A meta-analysis was conducted of 26 randomized, controlled trials of cognitive remediation in schizophrenia, including 1151 patients.[6] Cognitive remediation was associated with a medium effect size for cognitive performance.

Then, are there any synergistic effects of cognitive rehabilitation and antipsychotics? And when performing a cognitive rehabilitation, are there differences in the effect of cognitive rehabilitation depending on the type of antipsychotic drugs? A limited number of studies have examined the effects of antipsychotic medications in cognitive remediation. In one study, 36 subjects with treatment-refractory schizophrenia were exposed to a standardized token economy milieu, highly structured training of activities of daily living (ADL) and twice-daily training sessions in social and independent living skills.[7] Subjects taking risperidone and haloperidol showed significant improvements in ADL and neurocognitive performance, and no significant differences were found between groups. Twenty-two schizophrenia patients were randomly allocated to the cognitive remediation group or the intensive occupational therapy group.[8] In both groups, approximately half of the subjects were prescribed either typical antipsychotic or atypical antipsychotic drugs. Cognitive flexibility and memory were found to significantly improve in the cognitive remediation group compared to the intensive occupational therapy group. In the cognitive remediation group, atypical antipsychotics exhibited more improvement in cognitive flexibility than typical antipsychotics, but the difference was not significant.

As mentioned above, it is not yet possible to conclude on the effects of antipsychotics on neurocognitive rehabilitation or the synergistic effects of antipsychotics and neurocognitive rehabilitation. Although the effects of antipsychotics on neurocognitive functioning from the viewpoint of psychopharmacology might be guessed to some extent, this is difficult to demonstrate because of limited previous research findings. First, we carried out the exploratory research of how atypical antipsychotics influence neurocognitive functioning and the synergistic effects of antipsychotics and neurocognitive rehabilitation were observed.

Methods

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. References

Participants

Forty-three outpatients were diagnosed with schizophrenia or schizoaffective disorder and were aged 20–45 years at registration in a randomized trial of the effects of neurocognitive rehabilitation (study 1, n = 13) or a quasi-randomized experimental trial of the supported employment with neurocognitive rehabilitation (study 2, n = 30). Subjects did not report any of the following: (i) evidence of an organic central nervous system disorder; (ii) a history of drug or alcohol abuse; or (iii) mental retardation. All patients gave written informed consent to participate in the study, according to the procedures, which were approved by the ethics committee at each site. Subjects were engaged in computer-based neurocognitive rehabilitation for 12 weeks. They were divided into the following groups: (i) the control-risperidone group (CR group) (n = 13; study 1 n = 5, study 2 n = 8); the rehabilitation-risperidone group (RR group) (n = 9; study 1 n = 4, study 2 n = 5); (iii) the control-aripiprazole group (CA group) (n = 10; study 1 n = 4, study 2 n = 6); and (iv) the rehabilitation-aripiprazole group (RA group) (n = 11; study 1 n = 0, study 2 n = 11).

Psychiatric symptoms and demographic assessments

All patients were evaluated with the Positive and Negative Syndrome Scale (PANSS). Premorbid intelligence was estimated using the National Adult Reading Test Japanese version (JART).[9, 10]

Neurocognitive functioning assessment

The Japanese version of the Brief Assessment of Cognition in Schizophrenia (BACS-J) requires less than 35 min to complete in patients with schizophrenia.[11, 12] The BACS-J has been validated as a reliable and practical scale to evaluate neurocognitive functioning.[12] The verbal memory, working memory, motor speed, category instances, letter fluency, processing speed, and executive function domains were tested. All test measures were converted to standardized z-scores by setting the sample mean of each measure at baseline to zero and the standard deviation to 1.

Social functioning assessment

The Life Assessment Scale for the Mentally Ill (LASMI) was developed to assess disability in daily life or community functioning.[13, 14] The LASMI is composed of the following five categories: (i) daily living; (ii) interpersonal relations; (iii) work skills; (iv) endurance and stability; and (v) self-recognition. Each category is composed of several items, with each item being rated on a 5-point scale (no problem = 0 to a serious problem = 4). Lower scores indicate higher degrees of independent living in the community. In our study, the ‘Interpersonal Relations’ category (LASMI-I) and ‘Work’ category (LASMI-W) were used.

The above assessment is evaluated by psychiatrists or clinical psychologists.

Study 1

Using a central registration system, participants in six sites were randomized to either a neurocognitive rehabilitation group (n = 30) that was immediately treated, or to a wait-list control group (n = 31) that waited for 12 weeks before being treated. Subjects were engaged in computer-based cognitive exercises (cogpack version 6.0 Marker Software, Ladenburg, Germany), which provided practice across a broad range of neurocognitive functions, including attention and concentration, psychomotor speed, learning and memory, and executive functions. The trainers instructed participants about how to complete the cognitive exercises, provided encouragement, and suggested strategies for improving performance on challenging exercises. Sessions required approximately 60 min, with subjects typically completing two sessions per week for 12 weeks. In addition to computer exercises, subjects participated in one session of bridging group per week for 12 weeks. Topics in the bridging group included social skills training and preparation for community living, the role of cognition in job performance and problem-solving about compensatory strategies for dealing with common challenges on the job. Psychiatric symptoms, neurocognitive functioning and social functioning assessments were evaluated at baseline and at 12 weeks.

Study 2

The subjects took part in quasi-randomized experimental trials in 11 sites. Depending on recruitment periods, subjects were assigned to either a supported employment alone group (n = 57) or to a supported employment with neurocognitive rehabilitation group (n = 52). During the assessment phase, a thorough cognitive assessment of the participants was conducted, as well as recording a detailed employment history. During the cognitive training phase, subjects were engaged in two sessions of the same cognitive training per week for 12 weeks and took part in one session of bridging group per week for 12 weeks, as in study 1. During the job search planning phase, the supported employment specialist and participants met together to plan the job search, based on the participant's vocational preference. Following job attainment, the cognitive training specialist and subject discussed job support strategies to enhance the transfer of cognitive skills in the computer training exercises, and to minimize the effects of any persisting cognitive impairments. Psychiatric symptoms, neurocognitive functioning and social functioning assessments were evaluated at baseline and at 12 weeks.

Subjects extracted from study 1 or study 2 for this analysis

We defined antipsychotic medication as a participants' main drug treatment if it accounted for more than 70% of chlorpromazine mg equivalents (CPZeq) dose at baseline.[15] The four groups were made up of patients for whom 70% of CPZeq dose was risperidone or aripiprazole. Subjects were excluded if they exhibited any of the following: (i) the main drug was changed by more than 30% of CPZeq dose during cognitive training; or (ii) biperiden mg equivalents (BPDeq) dose was changed during cognitive training.

Statistical analyses

Group differences of demographic characteristics, psychiatric symptoms and neurocognitive functioning at baseline were examined with one-way anova and Bonferroni tests. Two-way anova with neurocognitive rehabilitation and antipsychotic medications as factors was used to compare changes in PANSS, BACS-J, and LASMI scores for 12 weeks. One-way anova was used to compare changes in PANSS, BACS-J, and LASMI during 12 weeks between the CR group and the RR group or between the CA group and the RA group.

Results

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. References

Demographic data (Table 1)

Table 1. Demographic data, psychiatric symptoms and neurocognitive functioning at baseline
 CR groupRR groupCA groupRA groupF
n = 13n = 9n = 10n = 11
MeanSDMeanSDMeanSDMeanSD
  1. BACS, Brief Assessment of Cognition in Schizophrenia; BPDeq, biperiden mg equivalents; CA group, control-aripiprazole group; CPZeq, chlorpromazine mg equivalents; CR group, control-risperidone group; JART, National Adult Reading Test Japanese version; PANSS, Positive and Negative Syndrome Scale; RA group: rehabilitation-aripiprazole group;RR group, rehabilitation-risperidone group.

Age (years)33.857.28366.5238.54.435.097.820.95
Duration of illness (months)15271.5112698.3313281.58115.6489.20.38
CPZeq (mg per day)474.23297.33461.11479.44395230.58363.71215.560.32
BPDeq (mg per day)1.311.840.671.120.10.320.450.822.01
JART (score)102.2710.9199.4412.22101.29.21101.1810.850.06
PANSS score         
Positive symptoms11.773.711.335.110.3413.643.561.25
Negative symptoms16.314.7913.564.3315.65.2319.364.572.60
General psychology26.9210.3625.226.6928.88.4834.098.342.04
Total5517.9250.1114.4154.715.6967.0913.542.25
BACS (Z-score)         
Verbal memory0.090.580.380.70.130.82–0.010.860.48
Working memory–0.090.890.631.330.521.250.050.941.10
Motor speed–0.230.980.280.890.440.64–0.430.712.63
Verbal fluency0.031.30.50.87–0.060.6–0.331.350.95
Processing speed0.331.150.090.97–0.120.84–0.270.910.81
Executive functions–0.621.54–0.431.450.280.730.410.682.09
Composite score–0.060.820.290.650.140.47–0.110.770.70

The results revealed no significant difference in demographic characteristics or psychiatric symptoms or neurocognitive functioning at baseline between the four groups. The mean duration of illness was 152.00 ± 71.51 months in the CR group, 126.00 ± 98.33 months in the RR group, 132.00 ± 81.58 months in the CA group, and 115.64 ± 89.20 months in the RA group.

Comparison of integrated effect of neurocognitive rehabilitation and antipsychotic medication (Table 2)

Table 2. Synergistic effect of neurocognitive rehabilitation and antipsychotic medication
 DrugControlRehabilitationF
 MeanSDMeanSDRehabilitationDrugDrug×rehabilitation
  1. Two-way factorial anova.

  2. *P < 0.05.

  3. APZ, aripiprazole; BACS, Brief Assessment of Cognition in Schizophrenia; LASMI, Life Assessment Scale for the Mentally Ill; PANSS, Positive and Negative Syndrome Scale; RIS, risperidone.

PANSS        
Positive symptomsRIS–0.921.38–1.671.584.30*2.681.31
APZ1.302.00–1.274.29   
Negative symptomsRIS–1.152.38–1.561.330.550.370.08
APZ–0.402.80–1.273.88   
General psychologyRIS–0.544.35–2.562.013.230.030.32
APZ0.705.48–3.187.61   
Total scoreRIS–2.626.33–5.783.703.900.650.61
APZ1.608.98–5.7312.59   
LASMI        
Interpersonal relationsRIS–1.923.04–4.226.831.971.220.02
APZ–0.505.02–2.364.43   
WorkRIS–0.851.14–2.334.094.56*0.320.58
APZ0.604.01–2.554.37   
BACS (Z-score)        
Verbal memoryRIS0.181.100.430.450.870.390.01
APZ0.350.460.570.90   
Working memoryRIS0.190.940.350.743.856.07*1.50
APZ–0.600.600.080.23   
Motor speedRIS0.560.670.400.431.431.474.38*
APZ–0.010.420.550.62   
Verbal fluencyRIS0.040.880.390.770.280.720.82
APZ0.470.650.380.86   
Processing speedRIS–0.100.380.360.693.471.161.64
APZ0.250.420.330.42   
Executive functionsRIS0.281.450.740.350.130.951.64
APZ0.370.450.110.62   
Composite scoreRIS0.160.410.400.312.950.020.22
APZ0.200.320.330.33   

A two-way anova with neurocognitive rehabilitation and antipsychotic medication as factors revealed a significant interaction effect on motor speed (F = 4.38, P ≤ 0.05). However, there were no main effects on motor speed. We found no significant interaction effect on social function and psychiatric symptoms.

We examined the effects of aripiprazole or risperidone on neurocognitive rehabilitation. Working memory (F = 12.5, P ≤ 0.01) and motor speed (F = 5.81, P ≤ 0.05) were significantly improved in the RA group compared with the CA group. We found no significant improvements between the CR group and the RR group.

Discussion

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. References

Synergistic effect of neurocognitive rehabilitation and antipsychotic medication

The synergistic effect of neurocognitive rehabilitation and aripiprazole was observed as an improvement of motor speed. No previous studies have examined the synergistic effect of neurocognitive rehabilitation and antipsychotic medication, including aripiprazole, and little research has examined the different neurocognitive effects of aripiprazole and risperidone. In a 12-month, open-label study, 698 patients with early-stage schizophrenia who were prescribed antipsychotics were assessed at baseline and at 12 months.[16] Risperidone and aripiprazole demonstrated greater improvements on the composite score, processing speed, working memory, executive functioning and visual memory at 12 months. There was no significant difference in improvement across all neurocognitive domains between risperidone and aripiprazole. In another previous study, a total of 129 patients with schizophrenia participating in two double-blind trials and one open-label trial comparing the effects of different atypical antipsychotics on cognition were assessed at admission and at 8 weeks.[17] Significant improvements in reaction time and cognition index were observed following risperidone treatment. Reaction time, reaction quality and cognition index significantly improved with aripiprazole treatment. In contrast, the study reported no significant differences in cognition index improvement between the risperidone and aripiprazole group. The details of the different neurocognitive effects of risperidone and aripiprazole are currently unclear. In one study, 85 inpatients with schizophrenia were randomly assigned to a cognitive remediation group or to a control condition.[18] Cognitive remediation was found to be associated with significant improvements on motor speed, verbal learning, and memory for 12 weeks. The integrated effect of neurocognitive rehabilitation and aripiprazole might be expected to improve motor speed. According to the findings of our present study, we plan to expand the scope of the present preliminary investigations by randomized controlled trial in future.

Effects of neurocognitive rehabilitation in aripiprazole

Working memory and motor speed significantly improved in the RA group compared with the CA group. Few previous studies have examined the neurocognitive effects of aripiprazole. Aripiprazole was reported to demonstrate greater improvement in composite scores, processing speed, working memory, executive functioning and visual memory at 12 months.[16] Aripiprazole is reported to exhibit a partial agonistic effect against the dopamine D2 receptor, and has a lower risk of extrapyramidal syndromes than other antipsychotics.[19, 20] In aripiprazole, the effect of neurocognitive rehabilitation might result in improvement of motor speed and working memory.

Effect of neurocognitive rehabilitation in risperidone

We found no significant improvements between the CR group and the RR group. A previous meta-analysis suggested that effect sizes for processing speed, working memory, learning, and delayed recall in risperidone were significant. In contrast, improvements in verbal fluency, vigilance and selective attention were found to be greater following quetiapine and olanzapine treatment, compared with risperidone.[21] In one study, patients with schizophrenia were randomly assigned to receive treatment with either quetiapine (n = 73) or risperidone (n = 97) for an 8-week period.[22] Scores on Part A of the Trail-making Test were significantly improved with risperidone compared with quetiapine. In one double-blind 14-week trial, schizophrenia patients were assigned to receive risperidone (n = 26), olanzapine (n = 26), clozapine (n = 24) or haloperidol (n = 25).[23] Risperidone yielded significant improvements in processing speed and attention (P < 0.03), but there were no significant differences between medication types. Among patients receiving risperidone, the effect of neurocognitive rehabilitation might result in improvement of processing speed. In future, we plan to examine the effects of neurocognitive rehabilitation in risperidone or aripiprazole to replicate the findings of this research, examining a greater number of subjects and using randomized trials of intervention and antipsychotic medication.

Limitations

The current study involves a number of potential limitations. First, the sample size was small. Second, the raters were not blind, meaning there is a possibility that some raters may have expected the neurocognitive rehabilitation group to exhibit more psychiatric symptoms, neurocognitive functioning and social functioning. Third, study 1 and 2 did not involve randomization of antipsychotic medication. Finally, all groups were prescribed an antipsychotic drug as their main treatment, but were not necessarily receiving only one drug. It will be important to further examine these findings, using randomized trials of intervention, with subjects prescribed a single antipsychotic medication.

Acknowledgment

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. References

This study was supported by a grant (2008-mind-public subscription-002) from the Japanese Ministry of Health, Labour and Welfare. The authors have no conflicts of interest to declare.

References

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. References
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