Improvement in negative symptoms and functional outcome ...Improvement in negative symptoms and functional outcome after a new generation cognitive remediation program: A randomized

Draft Manuscript for Review. Please review online at http://mc.manuscriptcentral.com/oup/szbltn

Improvement in negative symptoms and functional outcome

after a new generation cognitive remediation program: A randomized controlled trial

Journal: Schizophrenia Bulletin

Manuscript ID: Draft

Manuscript Type: Regular Article

Date Submitted by the Author: n/a

Complete List of Authors: Sanchez, Pedro; Hospital Psiquiátrico de Alava, Refractory Psychosis Unit; CIBERSAM, , Centro de Investigación Biomédica en Red de Salud Mental, ; University of the Basque Country, Department of Neuroscience Peña, Javier; University of Deusto, Bengoetxea, Eneritz; University of Deusto, Department Department of Foundations and Methods of Psychology Ojeda, Natalia; University of Deusto, Department Department of Foundations and Methods of Psychology Elizagarate, Edorta; Hospital Psiquiátrico de Alava, Refractory Psychosis Unit; CIBERSAM, , Centro de Investigación Biomédica en Red de Salud Mental, ; University of the Basque Country, Department of Neuroscience Ezcurra, Jesus; Hospital Psiquiátrico de Alava, Refractory Psychosis Unit Gutierrez, Miguel; Hospital Universitario Alava- Sede Santiago, Department of Psychiatry; University of the Basque Country, Department of Neuroscience; CIBERSAM, , Centro de Investigación Biomédica en Red de Salud Mental,

Keywords: schizophrenia, negative symptoms, functional outcome, cognitive rehabilitation, REHACOP

http://www.schizophreniabulletin.oupjournals.org

Schizophrenia Bulletin. For Peer Review Only

Cognitive rehabilitation in schizophrenia: A RCT

1

Improvement in negative symptoms and functional outcome after a new

generation cognitive remediation program: A randomized controlled trial

Pedro Sánchez a,b,c, Javier Peña d, Eneritz Bengoetxea d, Natalia Ojeda d *,

Edorta Elizagárate a,b,c, Jesus Ezcurra a, and Miguel Gutiérrez b,c,e

a Refractory Psychosis Unit, Hospital Psiquiátrico de Alava, C/ Alava, 43. 01006 Vitoria, Spain

b Department of Neuroscience, Psychiatry Section, School of Medicine and Odontology,

University of the Basque Country. Vizcaya, Spain.

c CIBERSAM, Centro de Investigación Biomédica en Red de Salud Mental

d Faculty of Psychology and Education, University of Deusto, Avda. Universidades, 24. 48007

Bilbao, Spain

e Department of Psychiatry, Hospital Universitario Alava- Sede Santiago, C/ Olaguibel, 29.

01006 Vitoria, Spain

* Corresponding author: Natalia Ojeda, Universidad de Deusto, Avda de las

Universidades 24, 48007 Bilbao (Spain). Phone: 34 944139000 (ext 2702).

Email: [email protected]

Word count of the abstract: 244

Word count of text body: 4,654

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Abstract

Cognitive remediation improves cognition in schizophrenia, but its effectiveness

on other relevant factors such as negative symptoms and functional outcome

has not been studied to the same degree.

Eigthy-four inpatients with schizophrenia were recruited from Alava Hospital

(Spain). All subjects underwent a baseline and a 3 months assessment

including neurocognition, clinical symptoms, insight, functional outcome (Global

Asessment of Functioning (GAF) and Disability Assessment Schedule (DAS-

WHO). Patients were randomly assigned to either neuropsychological

rehabilitation (REHACOP) or control group for 3 months in addition to treatment

as usual. REHACOP is an integrative Spanish program that taps all basic

cognitive functions. It included experts´ last suggestions about positive

feedback and activities of daily living in patients´ enviroment.

REHACOP group showed significantly greater improvements at 3 months in

neurocognition, negative symptoms, disorganization and emotional distress

measures compared to the control group (Cohen´s effect size for these

changes ranged from d = .47 for emotional distress to d = .58 for

disorganization symptyoms). REHACOP group also improved significantly in

both GAF (d = .61) and DAS-WHO total score (d = .57). More specifically, they

showed significant improvement in vocational outcome (d = .47), family contact

(d = .50) and social competence (d = .56).

In conclusion, neuropsychological rehabilitation may be useful for the reduction

of negative symptoms and functional disability in schizophrenia. These findings

support the feasibility of integrating neuropsychological rehabilitation into

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treatment as usual programs for patients with schizophrenia. Reasons for the

efficacy of this program are discussed.

Key Words: schizophrenia; negative symptoms; functional outcome; cognitive

rehabilitation; REHACOP.

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Introduction

Negative symptoms and cognitive impairment are two of the most

common dimensions in schizophrenia. More than 50% of patients with

schizophrenia suffer from either negative and/or cognitive symptoms 1 in the

prodomal phase 2, during psychosis 3 and even after the remission of positive

symptoms 4. In addition, negative and cognitive symptoms are supposed to be

strong predictors of transition to psychosis in ultra high-risk samples 5 and of

poorer prognosis and functional outcome 6. More specifically, it has been

suggested that the presence of negative symptoms in early stages is

associated with a more adverse course, more psychotic episodes and greater

impairment in adaptative life skills 7.

The NIMH-MATRICS consensus statement on negative symptoms 6

suggested that persistent and clinically significant negative symptoms are a

distinct and important therapeutic target. Unfortunately, although proven as an

important factor in schizophrenia, negative symptoms have received less

attention in the literature than positive symptoms 1. Moreover, first and second

antipsychotic drugs have demonstrated limited efficacy on the improvement of

negative symptoms 8, although new promising glutamatergic agents are being

explored to target negative symptoms 9. Therefore, as a result new treatments

efforts should be placed on negative symptoms 6.

A recent meta-analysis carried out by Wykes et al. 10 reported data of the

effectiveness of cognitive remediation on clinical symptoms in general, but not

on negative symptoms in particular. A closer inspection at studies included in

this meta-analysis and studies published after it, offers inconsistent results. In

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spite of using different modalities of cognitive remediation, some authors have

found positive significant effects on negative symptoms 11-13. However, there are

also other studies published that have not found evidence of cognitive

remediation efficacy on negative symptoms 14-20. Most of the programs used in

these clinical trials were not specifically designed to target improvement in

negative symptoms but focused on the amilioration of cognitive deficits and

their impact in daily living.

On the other hand, most authors agree that the ultimate goal of any

treatment is to improve the functional capacity and quality of life of patients 10.

According to the meta-analysis previously mentioned 10, cognitive remediation is

effective for improving functioning, although effect sizes obtained were small to

medium. As previously stated with negative symptoms, functioning was

included as a single construct in this meta-analysis. Therefore, we cannot

conclude if cognitive remediation is equally effective for different functional

outcome domains, such as social functioning, vocational outcome, or self-care

management. A closer review of the literature including also recent studies

published in this topic indicates that the most studied functioning domains were

vocational and occupational outcome. Data showed mainly positive

improvement regarding occupational outcome 13,16,19,21. These results suggest

that cognitive remediation can be an effective tool for improving work or

vocational outcome in psychosis.

Social functioning has also been analysed, but studies have shown more

inconsistent results. Some studies reported that cognitive remediation improved

social functioning 12,13,22 whereas others have not 18,23. Less attention has been

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paid to other outcome domains, such as self-care management or familly

contact. To the best of our knowledge, there is only one study that directly

addressed self-care management and has not informed of significant

improvements 17.

According to McGurk et al.´s meta-analysis and Roder´s research update

12,24, authors suggest that the use of a strategy learning method and transfer

techniques may increase the benefitial effect of the treatment. In addition, they

suggest that a combination of cognitive remediation with psychiatric

rehabilitation and social skills training might provide stronger effects, rather than

cognitive remediation programs alone. Spanish REHACOP is a new generation

multidimensional remediation program which includes these proposals with

specific emphasis on the implementation of learned skills into activities of daily

living. Besides the combination of strategy learning, drill and practice, the

patients are required to transfer obtained knowledge to a set of concrete

activities relevant in their lifes. In order to achieve this goal, patients combine

practice of activities of daily living in group, (during the rehabilitation program)

and homework activities at their real enviroment.

In the current study we aimed to evaluate the efficacy of cognitive

remediation with the REHACOP in schizophrenia. The primary targets of this

study were negative symptoms and functional outcome, including specific

domains such as self-care management, vocational outcome, family contact

and social competence.

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Methods

Participants

Eighty-four inpatients with schizophrenia were recruited from the Alava

Hospital. In order to be included in the study patients had to meet diagnostic

criteria for Schizophrenia according to American Psychiatric Association’s

Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text

Revision (DSM-IV-TR) 25. In addition, they had to show no evidence of alcohol

or drug abuse in the last 30 days, previous history of significant lack of

consciousness, mental retardation, and relevant neurological or medical

condition.

Ten days after admission, clinical, cognitive and functional evaluation

was carried out. Afterwards, they were randomly allocated to either the

REHACOP Group or the Control Group (see Figure 1). Assignment to the

program was conducted on the basis of a computer-generated randomization

list. Both groups received treatment as usual, consisted of individual case

management and medical review. All patients were voluntary and gave written

informed consent to participate in the study. The study protocol was approved

by the Ethics Committee at the Health Department of the Basque Mental Health

System in Spain.

Measures

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Clinical symptoms, neurocognitive performance and functional outcome

were assessed before and after treatment. Baseline assessments were carried

out when patients were stable in psychopathology and medication after intake

on the hospital. Post-treatment assessment was carried out within the first week

after completing the intervention. All raters were blind to treatment condition

and had no other role in the project that would undermine the blinding.

Clinical assessment

After admission, patients completed a psychiatric interview and

evaluation with the Spanish version 26 of Positive and Negative Syndrome Scale

(PANSS) 27, which was scored using a 5-factor model. The five components

were positive, negative, disorganization, excitement and emotional distress

(See 28 for details). The Premorbid Adjustment Scale (PAS) was administered to

obtain a measure of clinical premorbid adjustment. Insight was evaluated with

Schedule for the Assessment of Insight (SAI) 29. After the training period, inter-

rater reliability coefficients were obtained for the clinical scales (they ranged

from .83 for CGI to .91 for PANSS).

Cognitive Evaluation

Measures of cognitive functioning included tests to assess attention,

working memory, verbal learning and memory, verbal fluency, processing

speed and executive functioning. Our evaluation protocol consisted of the

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following tests: Digit Span, Symbol Search and Digit Symbol from the Wechsler

General Intelligence Scale (WAIS-III 30), Trail Making Test A and B 31, The

Hopkins Verbal Learning Test (form 2 & 4) 32, The Stroop Word and Color Test

33, and Verbal Fluency Subtest from Test Barcelona 34. We made a composite

score with the tests described above. All cognitive measures were converted

into Z-scores and the sign of some measures were adjusted so that higher

scores indicated better neurocognitive performance. The internal consistency of

these composite neurocognitive score was high (Cronbach´s alpha = .81). On

the other hand, the Accentuation Reading Test (TAP) 35, which is the Spanish

version of the National Adult Reading Test (NART), was also administered to

obtain an estimation of each patient´s premorbid abilities.

Functional Outcome

Functional disability was assessed with the Global Assessment of

Functioning (GAF) 36, The Clinical General Impression Scale (CGI) 37, and

Disability Assessment Schedule (DAS-WHO) 38 scales. The four functional

disability characteristic indicators offered by DAS-WHO were analyzed with the

aim of having a better understanding of functional disability and its

improvement: Self-Care Management, Social Competence, Vocational

Outcome and Family Contact.

Intervention

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Developed by Ojeda and Peña in 2007 39, the REHACOP program is the

first Spanish cognitive remediation program specifically designed for psychosis

and schizophrenia. REHACOP is a structured program based on paper-pencil

tasks, using the principles of restoration, compensation, and optimization with a

number of training procedures which gradually increased the level of cognitive

effort and demand. REHACOP trains patients in traditionally impaired cognitive

domains such as attention, memory, processing speed, language, and

executive functioning. Additionally, the program includes three units related to

functional outcome treatment: social skills training, activities of daily living and

psychoeducation. Patients´ relatives also take part in psychoeducation groups,

which provide them all with a better knowledge about the illness, ways to cope

with symptoms, early identifications of signs and relapse, and clinical and social

resources availability.

The REHACOP includes up to 150 different tasks (30 tasks per domain)

hierarchically organized in three levels of difficulty and subtypes of abilities to

be trained. Once a basic cognitive strategy has been trained and well acquired,

the therapist moves on to the next level. This characteristic enables patient´s

progression as performance feedback is provided in each session after tasks

are completed and the patient has access to the information about their level of

difficulty of the task. Each task includes fixed instructions for the therapist to be

read to the patients, verbal and visual materials, and the patient´s response

sheet for the answers. It also provides the therapist with a solution sheet for

tasks with non open responses to facilitate a fast correction and interpretation. It

also offers a graph representation about the patient´s progression that can be

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shown to the patient depending on the therapist´s criteria. In addition, patients

are required to put into practice obtained benefits with homework activities. The

format of the program allows both, the individual and the group administration

(between 5 and 8 patients per group), although for the purpose of this study, the

group administration was chosen.

In the present study, REHACOP´s group attended 90-minutes-long

sessions taking place at least three days per week. During three months,

patients are supposed to integrate the learning experience, to practice in real

life context and to bring to the sessions feedback about possible new difficulties

that must be faced. In this study, REHACOP groups were conducted by a

trained neuropsychologist, although the highly structured design, instructions

and materials could allow its administration by other trained professionals.

The Control Group consisted of treatment as usual along with group

activities including drawing, reading daily news, creating constructions using

different materials (such as paper or wood). These activities were accomplished

in group format and with the same frequency as the implementation of Rehacop

in the experimental group.

Data analysis

Normality of data was tested with Kolmogorov-Smirnov Test. All

variables resembled the normal distribution, with the exception of CGI which

was log-transformed for further analyses. Raw scores are presented for all

variables. χ2 test was used to analyse any differences between the two groups

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on gender, and ANOVA tests on sociodemographic and clinical variables at

baseline.

Repeated measures of multiple analysis of variance (MANOVA) was

performed for clinical, cognitive and functional variables with Group (REHACOP

vs Control Group) as the between subject factor and Time (pre-treatment and

post-treatment) as the within group factor. Main effects of Time (longitudinal

dimension), Group (cross-sectional dimension) and Time X Group (interaction

effect) were examined. Regression analyses were performed in order to

analyse predictors of functional changes. Significance level was set at .05. All

tests were two-tailed.

Results

Sociodemographic characteristics of the groups

The sociodemographic characteristics of the REHACOP group and

Control group are depicted in the Table 1. Differences between the groups were

analysed in order to control for the success of the randomization. There were

no significant differences between the groups in any of the sociodemographic

characteristics studied. Both groups were equivalent in term of age, gender

distribution, marital status, occupation, education, premorbid adjustment and

premorbid IQ. There were no significant differences in other clinical

characteristics such as age at onset, number of previous hospitalizations,

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schizophrenia diagnosis, alcohol and tobacco consumption or dose of

antipsychotic medication (mg/day chlorpromazine equivalents).

Clinical changes in REHACOP and Control groups after intervention.

As seen in table 2, both groups showed a similar pattern of clinical

symptom severity at baseline, as well as a general improvement in clinical

measures. However, REHACOP group improved significantly more than control

group, according to significant Group X Time interactions for negative

symptoms, disorganization symptoms and emotional distress, as well as

PANSS total score. Effect size of these changes fell mostly in the medium

range (negative symptoms d = .48, disorganization d = .58, emotional distress d

= .47 and PANSS total score d = .50). Group X Time interactions for CGI

scores, on the other hand, were not significant. Finally, although not significant,

there was a trend toward significance in insight.

As previously mentioned, we reported data for negative symptoms factor

according to Van der Gaag et al´s meta-analysis 28. However, in order to make

our results easier to compare to other studies that used the conventional

PANSS scores (positive, negative and general psychopathology) and possible

future meta-analyses, we decided to provide also results regarding this negative

symptoms scale (items N1 to N7). REHACOP group reduced negative

symptoms from 26.08 (SD=12.37) at baseline to 20.94 (SD=10.56) after

treatment, whereas control group reduced negative symptoms from 23.74

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(SD=9.57) to 21.63 (SD=10.24). Interaction effect was significant (F = 5.30, p <

.05), with Cohen´s effect size falling in the medium range (d = .51).

Functional outcome changes in REHACOP and Control groups after

intervention

As seen in table 3, both groups showed a similar pattern of functional

outcome at baseline, with a general pattern of improvement over the treatment

period. Repeated Measures of MANOVA revealed significant Group X Time

interactions in GAF and DAS-WHO, suggesting that REHACOP group showed

a significantly larger pre-post improvement than the control group. For

example, REHACOP group´s improvement in GAF was twice as much as the

improvement obtained by control group. The effect size for GAF was d = .61

and for DASWHO total score was d = .57.

A closer inspection at DAS-WHO´s specific domains showed significant

Group X Time interactions in vocational outcome (d = .47), family contact (d =

.50) and social competence (d = .56). On the other hand, self-care management

did not reach statistical significance.

Predictors of change in functional outcome

Changes in negative symptoms (B = -.58, p < .001) and cognition (B = -

.36, p < .05) predicted changes in GAF scores in REHACOP group, whereas

different predictors emerged from patients that received occoupational therapy.

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Only changes in negative symptoms (B = -.45, p < .001) predicted changes in

GAF scores among patients in control group. Changes in negative symtpoms (B

= .62, p < .001) predicted changes in CGI among patients in control group,

whereas changes in negative symptoms (B = .67, p < .001) and cognition (B =

.39, p < .01) predicted changes in CGI scores in REHACOP group.

Finally, negative symptoms (B = -.60, p < .001) and cognition (B = -.36, p

< .01) predicted changes in DAS-WHO scores in REHACOP group. Only

changes in negative symtpoms (B = -.45, p < .001) predicted changes in DAS-

WHO among patients in control group.

Discussion

The aim of the present study was to analyse the efficacy of a cognitive

remediation program which emphasizes the implementation of acquired skills

into activities of daily living, compared to other treatment options, in negative

symptoms and functional outcome.

In our study, patients attending cognitive remediation did not only

improve neurocognition, but also clinical symptoms and functional outcome.

Moreover, improvements in cognition and negative symptoms predicted the

changes in functional outcome in REHACOP group, but not in the Control

group. This general improvement cannot be justified by receiving more

professional attention, differences in medication, or by other sample

characteristics. The improvement can be neither attributed to the effect of the

number of hours of exposure to treatment, since both groups received

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equivalent ones, nor to group vs individual interventions as both formats were

alike.

Regarding clinical symptomatology mayor finding of this study is that

REHACOP significantly reduced patients´ negative symptoms. Those results

support previous studies that indicated improvements in negative symptoms

12,13,40-42 but not all 14-20. It is difficult to find a clear reason for these inconsistent

results since cognitive remediation has been administrated in the same

hetereogeneous way trough studies that found significant improvements in

negative symptoms and those who have not. Moreover, the specific

assessment tools used across these studies were similar too. McGurk et al. 43

indicated that only cognitive remediation programs that provide positive learning

experiences that boslter self-esteem and perceived self-efficacy have benefitial

effects on symptom improvement. Grant supported this idea by showing that

cognitive impairment imposes discouraging life experiences in patients 44.

Those experiences may lead them to perceive negative expectancies and

develop defeatist believes, especially among patients with schizophrenia.

Consequently, it is possible to suggest that the way cognitive rehabilitation is

provided has an important role in the improvement of negative symptoms. The

implementation of the REHACOP training in this study emphasized the

relevance of these variables.

This cognitive remediation program has several characteristics that can

provide patients with positive learning experiences. These characteristics

include exercises hierarchically organized depending on their difficulty. Based

on patients´ performance and degree of impairment, the therapist starts

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providing exercises and strategies that can be achieved in an adecuate way by

patients. Once that level is reinforced, the patient is challenged with new tasks

with progressively higher levels of difficulty. Therefore, activities´ difficulty only

increases once they are able to use learned strategies properly. Owing to

gradual learning, positive feedback, and the transfer of learned strategies to

their daily life activities (with homework), patients may feel themselves more

capable of overcoming daily problems caused by cognitive impairments. As a

result, they may be more encouraged to take part in activities that they tended

to avoid before.

Unexpectedly, the intervention with the REHACOP turned out to be an

effective tool for improving other clinical symptoms, namely emotional distress

and disorganization symptoms. Very few studies have previously found

significant improvement in disorganization symptoms 16,19,42. On the other hand,

opposite to previous studies that reported data on emotional distress 16,17, we

found significant improvement in emotional distress symptoms. Group support,

positive feedback, involvement of family members in patient´s treatment and the

improvement on other areas (such as neurocognitive performance and negative

symptoms) may have accounted for these positive results in emotional distress.

However, REHACOP did not produce significant improvements on

positive symptoms, excitement or insight. These results are consistent with

most similar studies 14-16,19,20,45. Therefore, it might be worth examining potential

variables relevant to these clinical symptoms to aim additional benefits in future

trials and overcome limitations of this intervention. For example, a future goal

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could include analyzing the benefit of adding specific relaxation training

techniques and determine its possible relation to excitement symptoms.

The other main purpose of this kind of intervention is usually to improve

patients´ functional outcome. Consistent with previous articles 10, the

improvement in the experimental group in functional outcome was significantly

greater than in the control group. Likewise, the intervention with the REHACOP

program enabled our sample to obtain unexpected higher rates in some used

assessment scales. In fact, far from other studies 22, participants in this trial

improved twice as much as control group in general functioning (GAF). The

benefit of the cognitive remediation intervention in this study could be reinforced

by the inclusion of strategy learning, transfer techniques and the combination

with treatment as usual. On the other hand, patients learned strategies related

to cognitive functioning. These strategies must be used by the patients again

during the social skills training and homework exercises. Thus, patients

achieved the generalization of acquired knowledge and obtained higher benefits

into their ordinary life activities.

Since functional outcome consists of many different domains, it is useful

to discriminate in greater detail the obtained information about functional

disability. Observed improvements in vocational outcome in our study match up

with most of the previous studies published in this field 13,16,19,21. Contrary to the

methodology of our study, however, most other groups have combined

cognitive remediation with various types of vocational rehabilitation in the

experimental group. Despite the absence of vocational rehabilitation,

REHACOP turned out to be effective as well. Only one of the mentioned studies

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13 did not combine cognitive remediation with vocational rehabilitation and

showed also positive results. In a similar way to us, Eack et al. 13 trained their

patients in various cognitive domains and social skills. In both studies, learned

strategies were generalized to patients´ daily living using homeworks and

therapists provided them with positive feedback. According to this fact, we may

hypothesize that mentioned characteristics can play an important role in the

improvement of vocational outcome.

However, the efficacy of cognitive remediation in social competence

improvement has been inconsistent. REHACOP improved patients´ social

competence as previous studies have done 13,22. Studies that have not found

positive changes in social competence 14,17,18,20 have some features in common,

including that most of them were administered individually, and none included

social skills or daily life activities. Therefore, the inclusion of social skills training

and working with other patients simultaneously with feed back from both, the

therapist and colleagues is shown as a key factor for improving social

competence.

Consistent with previous findings 17, REHACOP group did not

significantly improved self-care management when compared to control group.

However, the degree of improvement was reduced and the baseline status of

the groups in self-care (good enough) could have introduced a ceiling effect.

Unfortunately, none of the reviewed studies have reported data on family

contact, so very little is known about this functional domain. However, the family

involvement in rehabilitation process benefits the patients´ recovery and it

seems reasonable to think that a good management of the family intervention

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can contribute to the general patient´s status. Our cognitive remediation

program encourages relatives to take part in some group activities, so that,

family members improve their knowledge of the relative´s feelings and improve

their management, including fears and worries.

Despite its promising findings, this study has several limitations. Firstly,

we did not assess social cognition. At the beginning of the study, REHACOP

had not included yet a social cognition training unit. Social cognition unit has

just been recently included in REHACOP and we hope to show our results in

future studies. Secondly, the study lacks measures of subjective quality of life

and it is important to know if REHACOP has a significant influence on patients´

self-steem or self-efficacy. Finally, a longitudinal follow up must be carried out in

order to know if the effects of the treatments are maintained in the long-term.

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Conflict of Interest

The Authors declare that there are no conflicts of interest in relation to

the subject of this study.

Funding

This work was supported by Health Department of Basque Government

(grant number 2010111136) and Educational and Science Department of the

Basque Goverment (Researcher Training Program, grant number BFI09.123).

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Table 1. Sociodemographic and Diagnostic Differences of Participants by

Treatment Group (REHACOP; Control Group).

REHACOP Control Group Group

differences p

Age (years) 33.60 (9.4) 36.92 (10.5) F = 2.50 0.118

Years of education (years) 9.23 (2.7) 10.24 (2.8) F = 2.17 0.146

Gender: n (%)

Males

Females

27 (75.0%)

9 (25.0%)

37 (77.1%)

11 (22.9%)

χ2 = 0.05

0.824

Age at onset 22.28 (6.1) 22.04 (6.1) F = 0.03 0.863

Number of previous hospitalizations 7.11 (6.6) 8.98 (10.3) F = 0.89 0.349

Accentuation Reading Test (TAP) 18.50 (4.5) 19.56 (6.3) F = 0.67 0.414

Premorbid Adjustment (Cannon-Spor) 49.64 (25.5) 46.75 (22.2) F = 0.30 0.582

Dose of antipsychotic medication

(converted to mg/day chlorpromazine) 695.09 (362.6) 911.88 (922.9) F = 1.77 0.186

DSM-IV-TR: n (%)

Paranoid

Disorganized

Residual

Non specified

29 (80.6%)

4 (11.1%)

2 (5.6%)

1 (2.8)

40 (77.9%)

3 (6.3%)

3 (6.3%)

2 (4.2%)

χ2 = 0.73 0.866

Occupation: n (%)

Employed

Unemployed

Disabled

3 (8.3%)

9 (25.0%)

24 (66.7%)

2 (4.2%)

7 (14.6%)

39 (81.3%)

χ2 = 2.35 0.308

Marital Status: n (%)

Single

Married

Separated or divorced

33 (91.7%)

1 (2.1%)

2 (5.6%)

45 (93.8%)

1 (2.8%)

2 (4.2%)

χ2 = 0.13 0.935

Alcohol consumption (g/day) 0.92 (1.5) 0.96 (1.5) F = 0.06 0.809

Tobacco Smoking (cigarettes /day) 20.56 (11.2) 18.04 (12.4) F = 0.90 0.345

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Note. DSM-IV-TR = The Diagnostic and Statistical Manual of Mental Disorders 4th edition, Text

Revised.

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Table 2. Changes in Clinical Symptoms and Cognitive Functioning from Baseline to Postreatment by Treatment Group (REHACOP;

Control Group)

Mean (SD) Main Effect Group Main Effect Time Main Effect Group X Time

REHACOP Control Group F P F P F P

Positive Symptoms Pre 18.47 (1.2) 16.47 (1.1) 0.54 0.464 46.15 <0.001 2.10 0.151

Post 12.72 (1.1) 12.75 (0.9)

Negative Symptoms Pre 27.23 (1.7) 24.85 (1.5) 0.10 0.749 23.54 <0.001 4.89 0.030

Post 21.91 (1.6) 22.84 (1.4)

Disorganization Pre 17.03 (1.0) 14.13 (0.9) 1.58 0.212 32.27 <0.001 7.32 0.008

Post 12.91 (0.9) 12.67 (0.8)

Excitement Pre 12.61 (0.8) 9.56 (0.7) 7.45 0.008 27.72 <0.001 1.64 0.204

Post 9.36 (0.6) 7.58 (0.6)

Emotional Distress Pre 10.97 (0.9) 7.95 (0.8) 5.32 0.024 38.01 <0.001 4.42 0.039

Post 7.66 (0.6) 6.33 (0.6)

Insight Pre 6.09 (0.7) 6.31 (0.6) 0.15 0.694 41.81 <0.001 2.98 0.088

Post 8.64 (0.6) 7.79 (0.5)

PANSS-Total Pre 99.39 (4.9) 84.56 (4.28) 2.77 0.100 48.13 <0.001 4.71 0.033

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Post 74.83 (4.1) 71.70 (3.6)

Neurocognition Pre -0.11 (0.59) 0.13 (0.71) 0.90 0.769 0.12 0.734 13.15 <0.001

Post 0.09 (0.48) -0.09 (0.54)

Note. SD = Standard Deviation; PANSS = Positive and Negative Syndrome Scale; Neurocognition = composite score of previously described

neurocognitive tests.

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Table 3. Functional outcome from Baseline to Post-treatment by Treatment Group (REHACOP; Control Group).

Mean (SD) Main Effect Group Main Effect Time Main Effect Group X Time

REHACOP Control Group F P F P F P

GAF Pre 38.88 (2.5) 43.33 (2.2) 0.00 0.983 64.42 <0.001 5.64 0.020

Post 58.06 (3.1) 53.75 (2.8)

DAS-WHO Pre 14.50 (0.6) 13.70 (0.6) 0.03 0.855 63.08 <0.001 6.26 0.014

Post 10.50 (0.8) 11.63 (0.7)

CGI Pre 5.08 (0.3) 4.64 (0.2) 0.48 0.490 66.04 <0.001 2.74 0.102

Post 3.66 (0.2) 3.71 (0.2)

Self-Care Pre 2.70 (0.2) 2.40 (0.2) 0.04 0.851 16.44 <0.001 1.22 0.272

Post 2.11 (0.2) 2.07 (0.2)

Social Competence Pre 3.78 (0.2) 3.71 (0.2) 1.99 0.164 54.57 <0.001 5.90 0.017

Post 2.72 (0.2) 3.18 (0.2)

Vocational Outcome Pre 4.00 (0.2) 3.97 (0.2) 2.41 0.127 48.01 <0.001 4.28 0.042

Post 2.88 (0.2) 3.38 (0.2)

Family Contact Pre 3.72 (0.2) 3.46 (0.2) 0.11 0.746 64.64 <0.001 4.88 0.030

Post 2.47 (0.2) 2.76 (0.2)

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Note.SD = Standard Deviation; GAF = Global Assessment of Fucntioning; DAS-WHO = Disability Assessment Schedule from WHO; CGI = Clinical

General Impression Scale.

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Figure 1. Recruitment procedure and study profile/Participants´ flow card

N= 92

Baseline assessment

and randomization

N= 38 subjects assigned to the

REHACOP Group.

2 patients did not complete

treatment (One of them had a

diagnosis change and the

other suffered from a health

N= 54 subjects assigned to

the Control Group.

6 patients did not complete

treatment (2 were

discharged, 4 declined to

collaborate in the time 2

Final N= 36 Final N= 48

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