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Effects of cognitive remediation on neurocognitive functions and psychiatric symptoms in schizophrenia inpatients
Schizophrenia Research 142 (2012) 165–170
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Effects of cognitive remediation on neurocognitive functions and psychiatric symptoms in schizophrenia inpatients Manouchehr Gharaeipour a,⁎, BJ Scott b a b
Tehran University of Medical Sciences, Department of Psychology, Hazrat Rasoul Akram Hospital, Niayesh, Satar Khan, Tehran, Iran Pacific University, Forest Grove, OR, School of Professional Psychology, Hillsboro, OR, USA
a r t i c l e
i n f o
Article history: Received 7 March 2012 Received in revised form 21 August 2012 Accepted 27 September 2012 Available online 25 October 2012 Keywords: Neuropsychology Neurocognitive Schizophrenia Rehabilitation
a b s t r a c t Objective: Many individuals diagnosed with schizophrenia have significant neurocognitive deficits, especially in the areas of attention, memory, and executive function. These deficits may exacerbate patients' psychiatric symptoms. Cognitive remediation has shown efficacy in improving neurocognitive functioning and may lead to amelioration of psychiatric symptoms in persons with schizophrenia. Method: Forty-two schizophrenic inpatients were randomly assigned to either a cognitive remediation group (n = 21) or a control group (n = 21) and were assessed using a neuropsychological battery and symptom scales for depression, anxiety, and positive and negative symptoms of schizophrenia at baseline and after two months of participation in a cognitive remediation program. Results: The intervention group showed significant improvements in neuropsychological functioning, depression and negative symptoms of schizophrenia after the intervention compared to the control group. Conclusion: Results of the study provide support for cognitive remediation as an efficacious intervention to improve neurocognitive functioning and decrease psychiatric symptoms of schizophrenia. © 2012 Elsevier B.V. All rights reserved.
1. Introduction There is now overwhelming empirical evidence that schizophrenia has neurobiological underpinnings (Harrison and Weinberger, 2005; Keshavan et al., 2008) and is usually accompanied by neurocognitive deficits (Heinrichs and Zakzanis, 1998; Fioravanti et al., 2005; Dickinson et al., 2007; Kurtz et al., 2010). Evidence over the past 20 years has revealed that as many as 80% of patients with schizophrenia exhibit neurocognitive deficits on measures of attention, learning and memory, problem solving, executive function, language and/or sensory motor skills (Saykin et al., 1991, 1994; Green et al., 2000, 2004; Raffard et al., 2009). Cognitive remediation is concerned with enabling people with neurocognitive deficits to achieve their maximum potential (Wilson et al., 2009) and offers promise in the rehabilitation of neurocognitive impairments in schizophrenia. Several randomized controlled trials of cognitive remediation have been conducted among patients with schizophrenia, and recent reviews of the efficacy of cognitive remediation as a method to improve neurocognitive functioning in schizophrenia have generally been positive (Wykes et al., 2011). In addition, some studies have reported positive effects of cognitive remediation on psychiatric symptoms in Western cultures (Medalia
⁎ Corresponding author. Tel.: +98 9365075916; fax: +98 2166517118. E-mail addresses: [email protected] (M. Gharaeipour), bjscott@pacificu.edu (B.J. Scott). 0920-9964/$ – see front matter © 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.schres.2012.09.018
et al., 2000; Bellucci et al., 2002; McGurk et al., 2007; Lindenmayer et al., 2008). In Iran, so far, treatment of patients with schizophrenia is mostly limited to pharmacotherapy. Emerging interventions such as psychosocial rehabilitation are promising., as Yasrebi et al. (2009) showed that this can be an effective intervention for patients with schizophrenia in Iran. They demonstrated a significant decrease (p b 0.001) in negative symptoms as well as significant improvement (p b 0.001) in social skills for the experimental group in comparison with the control group, after three months of psychosocial rehabilitation. In addition, Yazdani et al. (2007) demonstrated that occupational therapy decreased negative symptoms of schizophrenia such as flat affect, mutism, apathy, and interpersonal isolation in an Iranian schizophrenic sample. There is a growing body of research that supports a relationship between neurocognitive functions and psychiatric symptoms (Berman et al., 1997; Kremen et al., 2000; Johnson-Selfridge and Zalewski, 2001; Waters et al., 2003; Heydebrand et al., 2004; Rund et al., 2004). It has been suggested that different symptom patterns represent different pathological processes (Liddle, 1987, 1992). A number of studies have addressed the neurocognitive correlates of symptoms of schizophrenia. The negative symptoms have been shown to correlate with poor generation or execution of cognitive strategies, slow responses on simple attention tasks, poor abstract reasoning and impaired set shifting (Heydebrand et al., 2004). The positive symptoms appear to correlate mainly with difficulties in inhibition (Waters et al., 2003). Perseveration (Spaulding, 1978) and processing speed deficits (Rund et al., 2004) also have been
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associated with the persistence of delusional beliefs. Depressive symptoms have been shown to correlate with attentional dysfunction, poor semantic encoding, and reduced verbal recall and recognition (Burt et al., 1995; Kindermann and Brown, 1997; Veiel, 1997). Adverse effects of anxiety on efficiency of cognitive processing depend on two central executive functions involving attentional control: inhibition and set-shifting (Eysenck et al., 2007). Set-shifting and inhibition efficiency are negatively related to anxiety (Visu-Petra et al., 2012). Overall, the presence of neurocognitive dysfunction appears to influence the manifestation of psychiatric symptoms. Therefore, improving neurocognitive functions by means of cognitive remediation may lead to improvement in clinical symptoms. This study evaluated the effects of a cognitive remediation program on neurocognitive functions and psychiatric symptoms among Iranian schizophrenic inpatients. We hypothesized that cognitive remediation, in addition to improving neurocognitive performance, would ameliorate psychiatric symptoms including positive and negative symptoms as well as depression and anxiety. 2. Methods 2.1. Participants Forty-two inpatients meeting DSM-IV (American Psychiatric Association, 2000) criteria for schizophrenia, as determined by the Structured Clinical Interview for DSM-IV (SCID; Spitzer et al., 1997), participated. Participants were recruited from consecutive admissions to the psychiatric ward of the Hazrat Rasoul Akram Hospital. Inclusion criteria were signed informed consent, age over 20 years, and being fluent in speaking, reading, and writing Farsi. Exclusion criteria included auditory or visual impairment, evidence of mental retardation, history of traumatic brain injury, presence or history of any neurologic illness, and substance abuse or dependence. See Table 1 for a summary of demographical and clinical characteristics of the two groups. 2.2. Design This study utilized a single-blind randomized controlled design. Participants, who all received standard hospital care, were randomly assigned to the cognitive remediation condition (n = 21) or the control condition (n = 21), independent of the assessors. Randomization was independently conducted by a Bachelor's level research assistant who was not involved in study treatments. All cognitive remediation group patients received the same intervention. Cognitive remediation exercises were conducted in one-hour group sessions held five times per week plus the group discussion
(total of six times per week) over a period of two months. Subjects in the control condition were engaged in group supportive therapy for the same amount of time that the participants in the cognitive rehabilitation condition engaged in remediation sessions. Group supportive therapy utilized an illness management and education approach that provided patients with psychoeducation about schizophrenia and taught applied coping strategies to reduce stress. The therapist introduced the modality as an exercise in social cooperation and understanding. There was no set agenda for the sessions. The patients were invited to bring up recent experiences, problems, or concerns to the group for discussion. Testing on measures occurred prior to random group assignment (baseline) and after a two month intervention (posttreatment). All tests and scales were administered, scored and interpreted by two trained raters with Master's degrees in clinical psychology who were blind to treatment conditions. 2.3. Materials 2.3.1. Neuropsychological tests Rey Auditory Verbal Learning Test (RAVLT; Lezak, 2012) assesses verbal learning and verbal memory. The Wisconsin Card Sorting Test (WCST; Heaton, 1981) assesses executive function. The numbers of categories completed and perseverative errors were calculated. Auditory Consonant Trigrams (ACT; Stuss et al., 1987) assesses verbal working memory. The Rey–Osterrieth Complex Figure Test (ROCF; Osterrieth, 1944; Rey, 1941) assesses visual learning and memory. It was administered using the copy and five-minute recall procedures using the Meyers and Meyers scoring system (1995b). The Trail Making Test (TMT, Parts A and B; Army Individual Test Battery, 1944; Baer and Blais, 2010) assesses attention and processing speed. 2.3.2. Psychiatric measures The Positive and Negative Syndrome Scale (PANNS; Kay et al., 1988) assesses clinical symptoms of schizophrenia. It includes 30 items on three subscales—Positive, Negative, and General psychopathology; the Positive and Negative symptom scales were analyzed in the current study. The Beck Depression Inventory-II (BDI-II; Beck et al., 1996) assesses severity of depression. The Beck Anxiety Inventory (BAI; Beck et al., 1988) assesses severity of anxiety. Total scores were analyzed for the BDI-II and BAI. 2.4. Cognitive remediation The program was made up of educational, experiential (trying out strategies) and reflective (group discussion) components. Patients were engaged in approximately 40 h of neurocognitive exercises that provided equal practice time in areas of attention and concentration,
Table 1 Demographical and clinical characteristics of groups. Variable
Rehabilitation
Control
Statistic df
p
1
.212
.404
1
.525
.467
1
.495
SD
t
df
p
1.63 3.43 5.66 4.56 5.99
−.312 −1.679 1.059 −2.079 .578
40 40 40 40 40
.757 .101 .296 .044 .566
%
N
%
11 10 9 12 16 5
52.38 47.62 42.86 57.14 76.20 23.80
7 14 7 14 14 7
33.33 66.67 33.33 66.67 66.67 33.33
Variable
Mean
SD
Mean
Number of hospitalization Education (years) Age (years) Age at first hospitalization (years) Duration of illness (months)
2.81 9.81 29.81 21.05 15.71
1.33 3.74 7.61 2.13 3.20
2.95 11.67 27.62 23.33 14.86
Marital status Employment Gender
Single Married Employed Unemployed Male Female
x2 1.556
N
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learning and memory, and executive functions. Sessions were conducted in a seminar format. At the start of each week the clinical team provided a preview of topics to be presented. The group facilitator usually had a handout and presented information on a whiteboard. Participants took notes, asked questions, shared experiences relating to the topic and offered explanations to each other. Participants were taught about various compensatory strategies relevant to their needs, and they were given the opportunity to practice these strategies. They were also encouraged to relate the tasks carried out within the exercise group to everyday activities. The exercises were extracted from the literature on neuropsychological rehabilitation (Champion, 2006; Wilson et al., 2009) and cognitive remediation protocols for schizophrenia (Wykes and Reeder, 2005). Elements of these programs were adapted from individual to group format and also to fit the specific needs and abilities of the participants and treatment setting. All materials were translated into Farsi using a forward and backward translation method by two high school English teachers who were bilingual. Cognitive remediation was delivered in cohorts of 11 patients and supervised by two hospital staff members, including a Master's level clinical psychologist and a Bachelor's level occupational therapist. 2.5. Overview of the remediation program Most sessions included (1) education/information and (2) practical tasks; some sessions also involved (3) a ‘homework’ task. Session 1: Education about attention Sessions 2–6: Strategies for managing attention •External environment strategies: contingent reinforcement, self-instructional statements, salience cues (Wykes and Reeder, 2005). Minimizing external distractions (Champion, 2006). •Internal environment strategies: importance of mood and physical health (e.g. pain) in relation to attention and concentration, fatigue/sleep management (Wilson et al., 2009). Session 7: Review of attention homework and practice tasks Session 8: Education about working memory Sessions 9–13: Strategies for managing working memory •Immediate memory training, chunking (Wilson et al., 2009). Session 14: Review of working memory homework and practice tasks Session 15: Education about memory Sessions 16–27: Strategies for managing memory •Internal strategies (encoding): making associations, visual imagery, mental retracing, and mindmap (Wilson et al., 2009). Errorless learning (Champion, 2006). •External strategies: use of external memory aids such as calendars and diaries (Wilson et al., 2009). Session 28: Review of memory homework and practice tasks Session 29: Education about executive functioning Sessions 30–39: Strategies for managing executive functioning •Cognitive flexibility (Champion, 2006). •Problem solving (Wykes and Reeder, 2005). Session 40: Review of executive homework and practice tasks
2.6. Statistical analysis To determine baseline differences between groups, we performed Pearson chi-square analyses for categorical variables and t-tests for continuous variables on demographic and clinical characteristics. A series of analyses of covariance (ANCOVAs) was conducted to test for between-group differences in change on the neurocognitive and symptom variables, with posttreatment scores as the dependent variable and baseline scores as a covariate. The fixed factor was treatment group. A composite measure of overall cognitive functioning was computed by standardizing scores on each of the cognitive measures (computing z-scores) and summing the z-scores. All scores were standardized on the baseline score. In order to investigate if improved cognition was associated with reduced psychiatric symptoms, we examined the association between
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changes in cognitive composite scores and changes in symptom scales for the cognitive remediation group using Pearson correlations. Analyses were conducted using the Statistical Package for Social Sciences (SPSS; Release 16.0). 3. Results Pearson chi-square analyses and t-tests between the two groups at baseline on demographic and clinical variables indicated no statistically significant differences, except for age at first hospitalization, for which the cognitive rehabilitation group had a slightly younger age (see Table 1). All participants in both groups completed the program and no one dropped out of the study. All participants received second generation antipsychotic medication. The groups were similar at baseline based on neurocognitive functions. No significant differences were found between groups on mean baseline PANSS (positive and negative), BDI–II, or BAI scores (Table 2). Severity of the psychiatric symptoms at baseline were nearly similar to previous studies (Setare et al., 2009). Results from the ANCOVAs evaluating change in neurocognitive functions and psychiatric symptoms after intervention between the two groups are summarized in Table 2. After controlling for baseline levels, significant effects were found for TMT (A, B), ACT, RAVLT (trials 1–5), ROCF (copy, delayed), and WCST (categories completed, perseverative errors). A significant effect was found for the cognitive composite score in the cognitive remediation group. There were no significant differences between groups on RAVLT delayed recall. Results indicated significant change scores on the PANSS Negative subscale, but no significant changes on the Positive subscale. There was a significant improvement in depressive symptoms but no significant changes on anxiety scores. Furthermore, neurocognitive improvement was significantly related to improvements in negative symptoms (df = 19; t = 1.85; p = .05), with patients who experienced larger neurocognitive gains also experiencing greater negative symptom improvement. Correlations were obtained between change scores on the PANSS Negative subscale and neuropsychological tests for the cognitive remediation group. Of these correlations, the PANSS Negative symptoms scale had the strongest correlation with WCST errors (r = 0.41). 4. Conclusion This study was designed to test the hypothesis that schizophrenia patients receiving cognitive remediation would, in addition to experiencing improvement in neurocognitive functioning, demonstrate decreased psychiatric symptoms. Results revealed that participants who received the cognitive remediation intervention showed improvement in neurocognitive functioning and greater reduction in psychiatric symptoms. Specifically, scores on all cognitive measures improved except for RAVLT delayed recall. With respect to psychiatric symptoms, negative symptoms and depression decreased, even though psychiatric symptoms were not the main target of cognitive remediation. Thus, their decrease may reflect the impact of changes in neurocognitive functioning. This study adds to the increasing evidence that neurocognitive impairment is associated with negative symptoms of schizophrenia. Johnson-Selfridge and Zalewski (2001) found a significant negative correlation between overall severity of negative symptoms and executive functioning. More recently, Heydebrand et al. (2004) found inverse relationships between the negative symptoms of schizophrenia and executive functioning, psychomotor speed, memory and verbal fluency. Kremen et al. (2000) found that, relative to neuropsychologically impaired patients, those who were classified as “neuropsychologically within normal limits” had a tendency (p b .06) toward fewer negative symptoms. However, the association of positive symptoms and
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Table 2 Changes in neurocognitive functions and psychiatric symptoms. Intervention group Baseline
Control group
Posttreatment
Baseline
Posttreatment
ANCOVA
M
SD
M
SD
M
SD
M
SD
F
df
p
Cognitive measures WCST Categoriesa Errorsb RAVLT Trials 1–5c Delayedd ROCF Copye Delayedf TMT Part-Ag Part-Bg ACTh Cognitive compositei
4.14 13.48 30.33 8.72 17.86 8.57 31.38 40.28 7.71 .000
1.31 5.12 5.30 3.33 4.82 2.69 8.36 10.32 1.74 .945
4.57 9.00 42.95 9.14 23.90 11.43 23.90 36.95 8.98 .020
1.25 3.75 5.654 2.93 4.37 3.60 5.80 6.27 1.59 1.01
3.76 11.33 33.43 8.81 18.67 9.38 30.48 39.38 6.95 −.003
1.51 4.85 5.74 3.59 5.54 1.88 6.90 12.94 2.48 1.03
3.62 9.71 38.52 8.33 20.29 9.09 26.90 40.11 7.04 .000
1.66 2.70 4.46 2.65 5.33 2.91 3.33 8.41 2.13 .965
4.17 4.55 5.88 .208 5.92 6.62 4.33 6.73 5.58 4.81
1,40 1.40 1,40 1,40 1,40 1,40 1,40 1,40 1,40 1,40
.048 .039 .020 .651 .020 .014 .044 .013 .023 .041
Symptom measures BDI-IIj BAIj PANSS Positivek Negativek
28.81 28.24 28.38 34.62
3.35 5.80 5.69 7.03
22.62 26.38 25.66 23.67
2.25 4.63 2.41 4.10
30.38 30.09 26.57 35.38
5.97 7.39 3.42 3.25
27.38 27.95 24.77 31.48
3.14 4.39 2.41 4.45
17.99 .101 2.72 16.03
1,40 1,40 1,40 1,40
.000 .753 .507 .000
Notes: WCST = Wisconsin Card Sorting Test; RAVLT = Rey Auditory Verbal Learning Test; ROCF = Rey–Osterrieth Complex Figure Test; TMT = Trail Making Test; ACT = Auditory Consonant Trigrams; BDI-II = Beck Depression Inventory-II; BAI = Beck Anxiety Inventory; PANSS = Positive and Negative Syndrome Scale. a Refers to the number of categories completed. Scores range from 0 to 6. b In responding to a stimulus characteristic that is incorrect. c Sum of words learned across trials 1–5 (maximum each trial = 15, total = 75). d 30-min delayed recall score (maximum score = 15). e The accuracy of the original copy (maximum score 36). f 30-min delayed-recall scores (maximum score 36). g Time in seconds required for completion of the test. h The number of letters correctly remembered after 5 second delay interval was tallied. The maximum score was 15. i Computed z scores of the all cognitive measures and summed those z scores separately for the baseline and posttreatment assessments. j Scores range from 0 to 63. k Scores range from 7 to 49.
cognition has been limited. Rund et al. (2004) found some relationships between levels of positive symptoms and processing speed in patients with early onset schizophrenia. Waters et al. (2003) found significant correlations between the severity of auditory hallucinations and performance on two tasks of inhibition. Positive symptoms have been found to co-occur with impaired auditory attention and verbal memory (Berman et al., 1997). Overall, the evidence is more in favor of independence between positive symptoms and neuropsychological deficits (O'Leary et al., 2000). Depressive symptoms of the intervention group compared to the control group significantly improved, but there were no significant changes in anxiety. Previous meta-analytic reviews have suggested a significant relationship between depression and memory impairment (Burt et al., 1995; Kindermann and Brown, 1997; Veiel, 1997). Depression has also been associated with significant impairments in executive functioning (Lockwood et al., 2002) and general cognitive functioning (Ravnkilde et al., 2002). On the other hand, high levels of anxiety have not been found to have significant detrimental effects on memory (Kizilbash et al., 2002). Similarly, Penadés et al. (2006) examined the effect of Cognitive Remediation Therapy (CRT) on neurocognition, and secondarily on symptomatology and psychosocial functioning, Cognitive Behavioral Therapy (CBT) was used as a control condition. They found that CRT produced an overall improvement in neurocognition (d = 0.5). However, the impact on symptomatology, especially depression and anxiety, was significant only for the CBT group. There was a medium effect size (d = 0.37) for changes in the cognitive composite score, which is somewhat less than found in previous studies. For this study, the proportion of patients in each group who showed ≥25% and ≥50% decreases in symptom severity on the PANSS negative score at post-treatment were calculated. Although both figures are arbitrary, most clinicians would probably agree that a 25% improvement is worthwhile and a 50% improvement
represents an important clinical change (Durham et al., 2003). No patients in either group showed ≥50% reduction, while a large proportion (76%) of patients in the cognitive remediation group showed ≥25% reduction. Consistent with previous studies (Johnson-Selfridge and Zalewski, 2001; Heydebrand et al., 2004), executive functioning was found to have a stronger effect than attention, working memory, verbal memory or visual memory on negative symptoms. Specifically, a greater number of categories achieved on the WCST were related to better ratings on the PANSS Negative scale. In contrast, Lecardeur et al. (2009) investigated changes in symptoms and cognition in patients with schizophrenia and related disorders who received one of two novel cognitive remediation therapies, one targeting mental state attribution (MSAT) and the other focusing on mental flexibility (MFT), compared with a control group given treatment as usual. An ANCOVA revealed significant differences between the 3 groups (F (2, 20) = 4.81, p = .020) for PANSS Positive scores. Paired comparisons showed that the MFT group had a significantly lower score than the MSAT group (p = .012) or the control group (p = .017). ANCOVA discerned no difference between the three groups for PANSS Negative scores (F (2, 20) = 2.07, p = .152). Although the results of this study provided some evidence of a mediational relationship between changes in neurocognition and symptoms, it is important to remember that correlational analysis of changes cannot disambiguate the direction of mediational relationships, and it is possible that a bidirectional relationship exists between improved neurocognition and symptoms. Cognitive remediation may have some beneficial effects on symptoms by providing positive learning experiences that serve to bolster self-esteem and self-efficacy for achieving personal goals, thereby improving depression. A recent meta-analysis of randomized controlled trials indicated that cognitive remediation improved mood (McGurk et al., 2007). Although negative symptoms are a frequent feature of
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schizophrenia, they also occur as concomitants of depression (Wagman et al., 1987), and therefore it's possible that negative symptoms improved because depressed symptoms improved. Based on this study and findings of other researchers, positive symptoms may be more amenable to other interventions (e.g., psychopharmacology) than to cognitive remediation. Nevertheless, the nature and quality of relationship between neurocognitive functions and psychiatric symptoms are still to be delineated. Overall, our findings provide support for the inclusion of cognitive remediation as a means of enhancing the effectiveness of therapeutic strategies for schizophrenic patients. The results of this study can be used in planning appropriate remediation and psychoeducational programs for schizophrenic patients in Iran and culturally similar populations. Obviously, these results should be viewed with caution. A limitation of this study was that there was no follow up after the intervention to indicate whether the changes held up over time. Moreover, it is possible that the intensity of engagement level in the control intervention was not equivalent to that in the treatment group, and it is also possible that the treatment group represented a qualitatively different sample due to differences in age at first hospitalization. In face of these methodological limitations discussed above, further studies with larger samples are needed to confirm the present results. Role of funding source None to declare. Contributors Gharaeipour designed the study, and wrote the protocol and manuscript. Dr. Scott wrote the revised manuscript. Conflict of interest None to declare. Acknowledgment We would like to express our gratitude to all participants involved in this study. Thank you also to the dedicated staff members of the Hazrat Rasoul Akram Hospital for their continued hard work.
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Schizophrenia Research journal homepage: www.elsevier.com/locate/schres
Effects of cognitive remediation on neurocognitive functions and psychiatric symptoms in schizophrenia inpatients Manouchehr Gharaeipour a,⁎, BJ Scott b a b
Tehran University of Medical Sciences, Department of Psychology, Hazrat Rasoul Akram Hospital, Niayesh, Satar Khan, Tehran, Iran Pacific University, Forest Grove, OR, School of Professional Psychology, Hillsboro, OR, USA
a r t i c l e
i n f o
Article history: Received 7 March 2012 Received in revised form 21 August 2012 Accepted 27 September 2012 Available online 25 October 2012 Keywords: Neuropsychology Neurocognitive Schizophrenia Rehabilitation
a b s t r a c t Objective: Many individuals diagnosed with schizophrenia have significant neurocognitive deficits, especially in the areas of attention, memory, and executive function. These deficits may exacerbate patients' psychiatric symptoms. Cognitive remediation has shown efficacy in improving neurocognitive functioning and may lead to amelioration of psychiatric symptoms in persons with schizophrenia. Method: Forty-two schizophrenic inpatients were randomly assigned to either a cognitive remediation group (n = 21) or a control group (n = 21) and were assessed using a neuropsychological battery and symptom scales for depression, anxiety, and positive and negative symptoms of schizophrenia at baseline and after two months of participation in a cognitive remediation program. Results: The intervention group showed significant improvements in neuropsychological functioning, depression and negative symptoms of schizophrenia after the intervention compared to the control group. Conclusion: Results of the study provide support for cognitive remediation as an efficacious intervention to improve neurocognitive functioning and decrease psychiatric symptoms of schizophrenia. © 2012 Elsevier B.V. All rights reserved.
1. Introduction There is now overwhelming empirical evidence that schizophrenia has neurobiological underpinnings (Harrison and Weinberger, 2005; Keshavan et al., 2008) and is usually accompanied by neurocognitive deficits (Heinrichs and Zakzanis, 1998; Fioravanti et al., 2005; Dickinson et al., 2007; Kurtz et al., 2010). Evidence over the past 20 years has revealed that as many as 80% of patients with schizophrenia exhibit neurocognitive deficits on measures of attention, learning and memory, problem solving, executive function, language and/or sensory motor skills (Saykin et al., 1991, 1994; Green et al., 2000, 2004; Raffard et al., 2009). Cognitive remediation is concerned with enabling people with neurocognitive deficits to achieve their maximum potential (Wilson et al., 2009) and offers promise in the rehabilitation of neurocognitive impairments in schizophrenia. Several randomized controlled trials of cognitive remediation have been conducted among patients with schizophrenia, and recent reviews of the efficacy of cognitive remediation as a method to improve neurocognitive functioning in schizophrenia have generally been positive (Wykes et al., 2011). In addition, some studies have reported positive effects of cognitive remediation on psychiatric symptoms in Western cultures (Medalia
⁎ Corresponding author. Tel.: +98 9365075916; fax: +98 2166517118. E-mail addresses: [email protected] (M. Gharaeipour), bjscott@pacificu.edu (B.J. Scott). 0920-9964/$ – see front matter © 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.schres.2012.09.018
et al., 2000; Bellucci et al., 2002; McGurk et al., 2007; Lindenmayer et al., 2008). In Iran, so far, treatment of patients with schizophrenia is mostly limited to pharmacotherapy. Emerging interventions such as psychosocial rehabilitation are promising., as Yasrebi et al. (2009) showed that this can be an effective intervention for patients with schizophrenia in Iran. They demonstrated a significant decrease (p b 0.001) in negative symptoms as well as significant improvement (p b 0.001) in social skills for the experimental group in comparison with the control group, after three months of psychosocial rehabilitation. In addition, Yazdani et al. (2007) demonstrated that occupational therapy decreased negative symptoms of schizophrenia such as flat affect, mutism, apathy, and interpersonal isolation in an Iranian schizophrenic sample. There is a growing body of research that supports a relationship between neurocognitive functions and psychiatric symptoms (Berman et al., 1997; Kremen et al., 2000; Johnson-Selfridge and Zalewski, 2001; Waters et al., 2003; Heydebrand et al., 2004; Rund et al., 2004). It has been suggested that different symptom patterns represent different pathological processes (Liddle, 1987, 1992). A number of studies have addressed the neurocognitive correlates of symptoms of schizophrenia. The negative symptoms have been shown to correlate with poor generation or execution of cognitive strategies, slow responses on simple attention tasks, poor abstract reasoning and impaired set shifting (Heydebrand et al., 2004). The positive symptoms appear to correlate mainly with difficulties in inhibition (Waters et al., 2003). Perseveration (Spaulding, 1978) and processing speed deficits (Rund et al., 2004) also have been
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associated with the persistence of delusional beliefs. Depressive symptoms have been shown to correlate with attentional dysfunction, poor semantic encoding, and reduced verbal recall and recognition (Burt et al., 1995; Kindermann and Brown, 1997; Veiel, 1997). Adverse effects of anxiety on efficiency of cognitive processing depend on two central executive functions involving attentional control: inhibition and set-shifting (Eysenck et al., 2007). Set-shifting and inhibition efficiency are negatively related to anxiety (Visu-Petra et al., 2012). Overall, the presence of neurocognitive dysfunction appears to influence the manifestation of psychiatric symptoms. Therefore, improving neurocognitive functions by means of cognitive remediation may lead to improvement in clinical symptoms. This study evaluated the effects of a cognitive remediation program on neurocognitive functions and psychiatric symptoms among Iranian schizophrenic inpatients. We hypothesized that cognitive remediation, in addition to improving neurocognitive performance, would ameliorate psychiatric symptoms including positive and negative symptoms as well as depression and anxiety. 2. Methods 2.1. Participants Forty-two inpatients meeting DSM-IV (American Psychiatric Association, 2000) criteria for schizophrenia, as determined by the Structured Clinical Interview for DSM-IV (SCID; Spitzer et al., 1997), participated. Participants were recruited from consecutive admissions to the psychiatric ward of the Hazrat Rasoul Akram Hospital. Inclusion criteria were signed informed consent, age over 20 years, and being fluent in speaking, reading, and writing Farsi. Exclusion criteria included auditory or visual impairment, evidence of mental retardation, history of traumatic brain injury, presence or history of any neurologic illness, and substance abuse or dependence. See Table 1 for a summary of demographical and clinical characteristics of the two groups. 2.2. Design This study utilized a single-blind randomized controlled design. Participants, who all received standard hospital care, were randomly assigned to the cognitive remediation condition (n = 21) or the control condition (n = 21), independent of the assessors. Randomization was independently conducted by a Bachelor's level research assistant who was not involved in study treatments. All cognitive remediation group patients received the same intervention. Cognitive remediation exercises were conducted in one-hour group sessions held five times per week plus the group discussion
(total of six times per week) over a period of two months. Subjects in the control condition were engaged in group supportive therapy for the same amount of time that the participants in the cognitive rehabilitation condition engaged in remediation sessions. Group supportive therapy utilized an illness management and education approach that provided patients with psychoeducation about schizophrenia and taught applied coping strategies to reduce stress. The therapist introduced the modality as an exercise in social cooperation and understanding. There was no set agenda for the sessions. The patients were invited to bring up recent experiences, problems, or concerns to the group for discussion. Testing on measures occurred prior to random group assignment (baseline) and after a two month intervention (posttreatment). All tests and scales were administered, scored and interpreted by two trained raters with Master's degrees in clinical psychology who were blind to treatment conditions. 2.3. Materials 2.3.1. Neuropsychological tests Rey Auditory Verbal Learning Test (RAVLT; Lezak, 2012) assesses verbal learning and verbal memory. The Wisconsin Card Sorting Test (WCST; Heaton, 1981) assesses executive function. The numbers of categories completed and perseverative errors were calculated. Auditory Consonant Trigrams (ACT; Stuss et al., 1987) assesses verbal working memory. The Rey–Osterrieth Complex Figure Test (ROCF; Osterrieth, 1944; Rey, 1941) assesses visual learning and memory. It was administered using the copy and five-minute recall procedures using the Meyers and Meyers scoring system (1995b). The Trail Making Test (TMT, Parts A and B; Army Individual Test Battery, 1944; Baer and Blais, 2010) assesses attention and processing speed. 2.3.2. Psychiatric measures The Positive and Negative Syndrome Scale (PANNS; Kay et al., 1988) assesses clinical symptoms of schizophrenia. It includes 30 items on three subscales—Positive, Negative, and General psychopathology; the Positive and Negative symptom scales were analyzed in the current study. The Beck Depression Inventory-II (BDI-II; Beck et al., 1996) assesses severity of depression. The Beck Anxiety Inventory (BAI; Beck et al., 1988) assesses severity of anxiety. Total scores were analyzed for the BDI-II and BAI. 2.4. Cognitive remediation The program was made up of educational, experiential (trying out strategies) and reflective (group discussion) components. Patients were engaged in approximately 40 h of neurocognitive exercises that provided equal practice time in areas of attention and concentration,
Table 1 Demographical and clinical characteristics of groups. Variable
Rehabilitation
Control
Statistic df
p
1
.212
.404
1
.525
.467
1
.495
SD
t
df
p
1.63 3.43 5.66 4.56 5.99
−.312 −1.679 1.059 −2.079 .578
40 40 40 40 40
.757 .101 .296 .044 .566
%
N
%
11 10 9 12 16 5
52.38 47.62 42.86 57.14 76.20 23.80
7 14 7 14 14 7
33.33 66.67 33.33 66.67 66.67 33.33
Variable
Mean
SD
Mean
Number of hospitalization Education (years) Age (years) Age at first hospitalization (years) Duration of illness (months)
2.81 9.81 29.81 21.05 15.71
1.33 3.74 7.61 2.13 3.20
2.95 11.67 27.62 23.33 14.86
Marital status Employment Gender
Single Married Employed Unemployed Male Female
x2 1.556
N
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learning and memory, and executive functions. Sessions were conducted in a seminar format. At the start of each week the clinical team provided a preview of topics to be presented. The group facilitator usually had a handout and presented information on a whiteboard. Participants took notes, asked questions, shared experiences relating to the topic and offered explanations to each other. Participants were taught about various compensatory strategies relevant to their needs, and they were given the opportunity to practice these strategies. They were also encouraged to relate the tasks carried out within the exercise group to everyday activities. The exercises were extracted from the literature on neuropsychological rehabilitation (Champion, 2006; Wilson et al., 2009) and cognitive remediation protocols for schizophrenia (Wykes and Reeder, 2005). Elements of these programs were adapted from individual to group format and also to fit the specific needs and abilities of the participants and treatment setting. All materials were translated into Farsi using a forward and backward translation method by two high school English teachers who were bilingual. Cognitive remediation was delivered in cohorts of 11 patients and supervised by two hospital staff members, including a Master's level clinical psychologist and a Bachelor's level occupational therapist. 2.5. Overview of the remediation program Most sessions included (1) education/information and (2) practical tasks; some sessions also involved (3) a ‘homework’ task. Session 1: Education about attention Sessions 2–6: Strategies for managing attention •External environment strategies: contingent reinforcement, self-instructional statements, salience cues (Wykes and Reeder, 2005). Minimizing external distractions (Champion, 2006). •Internal environment strategies: importance of mood and physical health (e.g. pain) in relation to attention and concentration, fatigue/sleep management (Wilson et al., 2009). Session 7: Review of attention homework and practice tasks Session 8: Education about working memory Sessions 9–13: Strategies for managing working memory •Immediate memory training, chunking (Wilson et al., 2009). Session 14: Review of working memory homework and practice tasks Session 15: Education about memory Sessions 16–27: Strategies for managing memory •Internal strategies (encoding): making associations, visual imagery, mental retracing, and mindmap (Wilson et al., 2009). Errorless learning (Champion, 2006). •External strategies: use of external memory aids such as calendars and diaries (Wilson et al., 2009). Session 28: Review of memory homework and practice tasks Session 29: Education about executive functioning Sessions 30–39: Strategies for managing executive functioning •Cognitive flexibility (Champion, 2006). •Problem solving (Wykes and Reeder, 2005). Session 40: Review of executive homework and practice tasks
2.6. Statistical analysis To determine baseline differences between groups, we performed Pearson chi-square analyses for categorical variables and t-tests for continuous variables on demographic and clinical characteristics. A series of analyses of covariance (ANCOVAs) was conducted to test for between-group differences in change on the neurocognitive and symptom variables, with posttreatment scores as the dependent variable and baseline scores as a covariate. The fixed factor was treatment group. A composite measure of overall cognitive functioning was computed by standardizing scores on each of the cognitive measures (computing z-scores) and summing the z-scores. All scores were standardized on the baseline score. In order to investigate if improved cognition was associated with reduced psychiatric symptoms, we examined the association between
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changes in cognitive composite scores and changes in symptom scales for the cognitive remediation group using Pearson correlations. Analyses were conducted using the Statistical Package for Social Sciences (SPSS; Release 16.0). 3. Results Pearson chi-square analyses and t-tests between the two groups at baseline on demographic and clinical variables indicated no statistically significant differences, except for age at first hospitalization, for which the cognitive rehabilitation group had a slightly younger age (see Table 1). All participants in both groups completed the program and no one dropped out of the study. All participants received second generation antipsychotic medication. The groups were similar at baseline based on neurocognitive functions. No significant differences were found between groups on mean baseline PANSS (positive and negative), BDI–II, or BAI scores (Table 2). Severity of the psychiatric symptoms at baseline were nearly similar to previous studies (Setare et al., 2009). Results from the ANCOVAs evaluating change in neurocognitive functions and psychiatric symptoms after intervention between the two groups are summarized in Table 2. After controlling for baseline levels, significant effects were found for TMT (A, B), ACT, RAVLT (trials 1–5), ROCF (copy, delayed), and WCST (categories completed, perseverative errors). A significant effect was found for the cognitive composite score in the cognitive remediation group. There were no significant differences between groups on RAVLT delayed recall. Results indicated significant change scores on the PANSS Negative subscale, but no significant changes on the Positive subscale. There was a significant improvement in depressive symptoms but no significant changes on anxiety scores. Furthermore, neurocognitive improvement was significantly related to improvements in negative symptoms (df = 19; t = 1.85; p = .05), with patients who experienced larger neurocognitive gains also experiencing greater negative symptom improvement. Correlations were obtained between change scores on the PANSS Negative subscale and neuropsychological tests for the cognitive remediation group. Of these correlations, the PANSS Negative symptoms scale had the strongest correlation with WCST errors (r = 0.41). 4. Conclusion This study was designed to test the hypothesis that schizophrenia patients receiving cognitive remediation would, in addition to experiencing improvement in neurocognitive functioning, demonstrate decreased psychiatric symptoms. Results revealed that participants who received the cognitive remediation intervention showed improvement in neurocognitive functioning and greater reduction in psychiatric symptoms. Specifically, scores on all cognitive measures improved except for RAVLT delayed recall. With respect to psychiatric symptoms, negative symptoms and depression decreased, even though psychiatric symptoms were not the main target of cognitive remediation. Thus, their decrease may reflect the impact of changes in neurocognitive functioning. This study adds to the increasing evidence that neurocognitive impairment is associated with negative symptoms of schizophrenia. Johnson-Selfridge and Zalewski (2001) found a significant negative correlation between overall severity of negative symptoms and executive functioning. More recently, Heydebrand et al. (2004) found inverse relationships between the negative symptoms of schizophrenia and executive functioning, psychomotor speed, memory and verbal fluency. Kremen et al. (2000) found that, relative to neuropsychologically impaired patients, those who were classified as “neuropsychologically within normal limits” had a tendency (p b .06) toward fewer negative symptoms. However, the association of positive symptoms and
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Table 2 Changes in neurocognitive functions and psychiatric symptoms. Intervention group Baseline
Control group
Posttreatment
Baseline
Posttreatment
ANCOVA
M
SD
M
SD
M
SD
M
SD
F
df
p
Cognitive measures WCST Categoriesa Errorsb RAVLT Trials 1–5c Delayedd ROCF Copye Delayedf TMT Part-Ag Part-Bg ACTh Cognitive compositei
4.14 13.48 30.33 8.72 17.86 8.57 31.38 40.28 7.71 .000
1.31 5.12 5.30 3.33 4.82 2.69 8.36 10.32 1.74 .945
4.57 9.00 42.95 9.14 23.90 11.43 23.90 36.95 8.98 .020
1.25 3.75 5.654 2.93 4.37 3.60 5.80 6.27 1.59 1.01
3.76 11.33 33.43 8.81 18.67 9.38 30.48 39.38 6.95 −.003
1.51 4.85 5.74 3.59 5.54 1.88 6.90 12.94 2.48 1.03
3.62 9.71 38.52 8.33 20.29 9.09 26.90 40.11 7.04 .000
1.66 2.70 4.46 2.65 5.33 2.91 3.33 8.41 2.13 .965
4.17 4.55 5.88 .208 5.92 6.62 4.33 6.73 5.58 4.81
1,40 1.40 1,40 1,40 1,40 1,40 1,40 1,40 1,40 1,40
.048 .039 .020 .651 .020 .014 .044 .013 .023 .041
Symptom measures BDI-IIj BAIj PANSS Positivek Negativek
28.81 28.24 28.38 34.62
3.35 5.80 5.69 7.03
22.62 26.38 25.66 23.67
2.25 4.63 2.41 4.10
30.38 30.09 26.57 35.38
5.97 7.39 3.42 3.25
27.38 27.95 24.77 31.48
3.14 4.39 2.41 4.45
17.99 .101 2.72 16.03
1,40 1,40 1,40 1,40
.000 .753 .507 .000
Notes: WCST = Wisconsin Card Sorting Test; RAVLT = Rey Auditory Verbal Learning Test; ROCF = Rey–Osterrieth Complex Figure Test; TMT = Trail Making Test; ACT = Auditory Consonant Trigrams; BDI-II = Beck Depression Inventory-II; BAI = Beck Anxiety Inventory; PANSS = Positive and Negative Syndrome Scale. a Refers to the number of categories completed. Scores range from 0 to 6. b In responding to a stimulus characteristic that is incorrect. c Sum of words learned across trials 1–5 (maximum each trial = 15, total = 75). d 30-min delayed recall score (maximum score = 15). e The accuracy of the original copy (maximum score 36). f 30-min delayed-recall scores (maximum score 36). g Time in seconds required for completion of the test. h The number of letters correctly remembered after 5 second delay interval was tallied. The maximum score was 15. i Computed z scores of the all cognitive measures and summed those z scores separately for the baseline and posttreatment assessments. j Scores range from 0 to 63. k Scores range from 7 to 49.
cognition has been limited. Rund et al. (2004) found some relationships between levels of positive symptoms and processing speed in patients with early onset schizophrenia. Waters et al. (2003) found significant correlations between the severity of auditory hallucinations and performance on two tasks of inhibition. Positive symptoms have been found to co-occur with impaired auditory attention and verbal memory (Berman et al., 1997). Overall, the evidence is more in favor of independence between positive symptoms and neuropsychological deficits (O'Leary et al., 2000). Depressive symptoms of the intervention group compared to the control group significantly improved, but there were no significant changes in anxiety. Previous meta-analytic reviews have suggested a significant relationship between depression and memory impairment (Burt et al., 1995; Kindermann and Brown, 1997; Veiel, 1997). Depression has also been associated with significant impairments in executive functioning (Lockwood et al., 2002) and general cognitive functioning (Ravnkilde et al., 2002). On the other hand, high levels of anxiety have not been found to have significant detrimental effects on memory (Kizilbash et al., 2002). Similarly, Penadés et al. (2006) examined the effect of Cognitive Remediation Therapy (CRT) on neurocognition, and secondarily on symptomatology and psychosocial functioning, Cognitive Behavioral Therapy (CBT) was used as a control condition. They found that CRT produced an overall improvement in neurocognition (d = 0.5). However, the impact on symptomatology, especially depression and anxiety, was significant only for the CBT group. There was a medium effect size (d = 0.37) for changes in the cognitive composite score, which is somewhat less than found in previous studies. For this study, the proportion of patients in each group who showed ≥25% and ≥50% decreases in symptom severity on the PANSS negative score at post-treatment were calculated. Although both figures are arbitrary, most clinicians would probably agree that a 25% improvement is worthwhile and a 50% improvement
represents an important clinical change (Durham et al., 2003). No patients in either group showed ≥50% reduction, while a large proportion (76%) of patients in the cognitive remediation group showed ≥25% reduction. Consistent with previous studies (Johnson-Selfridge and Zalewski, 2001; Heydebrand et al., 2004), executive functioning was found to have a stronger effect than attention, working memory, verbal memory or visual memory on negative symptoms. Specifically, a greater number of categories achieved on the WCST were related to better ratings on the PANSS Negative scale. In contrast, Lecardeur et al. (2009) investigated changes in symptoms and cognition in patients with schizophrenia and related disorders who received one of two novel cognitive remediation therapies, one targeting mental state attribution (MSAT) and the other focusing on mental flexibility (MFT), compared with a control group given treatment as usual. An ANCOVA revealed significant differences between the 3 groups (F (2, 20) = 4.81, p = .020) for PANSS Positive scores. Paired comparisons showed that the MFT group had a significantly lower score than the MSAT group (p = .012) or the control group (p = .017). ANCOVA discerned no difference between the three groups for PANSS Negative scores (F (2, 20) = 2.07, p = .152). Although the results of this study provided some evidence of a mediational relationship between changes in neurocognition and symptoms, it is important to remember that correlational analysis of changes cannot disambiguate the direction of mediational relationships, and it is possible that a bidirectional relationship exists between improved neurocognition and symptoms. Cognitive remediation may have some beneficial effects on symptoms by providing positive learning experiences that serve to bolster self-esteem and self-efficacy for achieving personal goals, thereby improving depression. A recent meta-analysis of randomized controlled trials indicated that cognitive remediation improved mood (McGurk et al., 2007). Although negative symptoms are a frequent feature of
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schizophrenia, they also occur as concomitants of depression (Wagman et al., 1987), and therefore it's possible that negative symptoms improved because depressed symptoms improved. Based on this study and findings of other researchers, positive symptoms may be more amenable to other interventions (e.g., psychopharmacology) than to cognitive remediation. Nevertheless, the nature and quality of relationship between neurocognitive functions and psychiatric symptoms are still to be delineated. Overall, our findings provide support for the inclusion of cognitive remediation as a means of enhancing the effectiveness of therapeutic strategies for schizophrenic patients. The results of this study can be used in planning appropriate remediation and psychoeducational programs for schizophrenic patients in Iran and culturally similar populations. Obviously, these results should be viewed with caution. A limitation of this study was that there was no follow up after the intervention to indicate whether the changes held up over time. Moreover, it is possible that the intensity of engagement level in the control intervention was not equivalent to that in the treatment group, and it is also possible that the treatment group represented a qualitatively different sample due to differences in age at first hospitalization. In face of these methodological limitations discussed above, further studies with larger samples are needed to confirm the present results. Role of funding source None to declare. Contributors Gharaeipour designed the study, and wrote the protocol and manuscript. Dr. Scott wrote the revised manuscript. Conflict of interest None to declare. Acknowledgment We would like to express our gratitude to all participants involved in this study. Thank you also to the dedicated staff members of the Hazrat Rasoul Akram Hospital for their continued hard work.
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