Neurocognitive Training Integrated in OPUS Treatment Versus OPUS Treatment-as-usual
Condition: Schizophrenia
MeSH terms: Schizophrenia
Study type: Interventional
Phase: Phase 3

Summary: 
      The study examines the effect of cognitive training on cognitive functioning and everyday
      competencies of patients with schizophrenia.

      120 patients are expected to be included in this randomized controlled trial running at two
      sites in Denmark starting January 2007 The effect of a 16-week, manualized program of
      cognitive training integrated in a comprehensive psychosocial treatment (OPUS) for
      first-episode schizophrenia patients is compared with the effect of standard treatment
      (OPUS). A six month follow-up assessment is conducted to investigate a possible long-term
      learning effect of cognitive training.

      Blinded assessments include the MATRICS Consensus Cognitive Battery and a co-primary outcome
      measure of cognitive improvement: A translated version of the UCSD Performance-based Skills
      Assessment (UPSA) adjusted to a Danish context.

      The cognitive training consists of four modules focusing on the domain of attention,
      executive functioning, learning and memory. Module 1 and 2 are based on computer-assisted
      training tasks, and the following modules focus on more practical everyday tasks and calendar
      training. Cognitive training takes place twice a week and every other week the patient and
      trainer engage in a dialogue on the patient's cognitive difficulties, motivational goals and
      his/her progress in competence level.

      The use of errorless learning principles, scaffolding and attentional externalisation aims at
      improving the patients' performance on cognitive and everyday tasks by learning to apply
      compensation techniques as well as limiting dysfunctional uses of available cognitive
      ressources (i.e. excessive self-focus, rumination).

      The study will provide MATRICS Consensus Cognitive Battery results from a relatively large
      Danish sample of first-episode schizophrenia and contribute with valuable normative data on
      the UPSA.

      It is hypothesized that cognitive training integrated in OPUS treatment enhances both
      cognitive and everyday competence of patients more than OPUS treatment alone. Expectations
      are that cognitive training will demonstrate a small to moderate effect on cognitive
      functioning and a moderate effect on everyday functioning as measured with the UPSA.
      Moreover, patients allocated to cognitive training are expected to show an improvement in
      self-esteem.
    

Detailed description: 
      Neurocognition and competence in schizophrenia A randomized controlled trial of cognitive
      training (CT) integrated in OPUS treatment versus OPUS treatment-as-usual

      The presence of cognitive deficits in schizophrenia It is a well-established fact that
      cognitive deficits play a major role in functional outcome in schizophrenia (Keefe et al,
      2006; Gold, 2004). Up to 85 % patients demonstrate cognitive dysfunctions in the range of
      1½-2 SD below norm (Fagerlund, 2004; Corrigan & Penn, 2001; Heinrichs & Zankanis, 1998).
      Cognitive dysfunctions associated with schizophrenia involve attention, information
      processing, memory, and executive functions leading to difficulties in learning and poor
      problem solving abilities.

      Evidence for the effect of rehabilitation on everyday competencies In spite of the severely
      debilitating cognitive dysfunctions, a relatively large number of patients have shown
      themselves capable of acquiring new abilities (e.g. Kern et al, 2005; Sartory et al, 2005;
      Ueland & Rund, 2004; Krabbendam & Aleman, 2003, Pilling et al, 2002, Harvey & Sharma, 2001;
      Tsang & Pearson, 2001, Danion et al, 2001, Bell et al, 2003, Wykes et al, 1999, 2003).
      Research has shown that training in symptom handling, social proficiency training, and
      supportive provisions in occupational relations apparently can help patients with
      schizophrenia to function in their daily lives, learn solving concrete practical and social
      tasks, and manage relatively independently. These improvements enhance self-esteem.

      Effect studies of cognitive rehabilitation A Cochrane review done by Hayes & McGrath (2000)
      include three small randomized controlled trials and fails to provide conclusive data on
      evidence for or against cognitive training as a treatment for schizophrenia.

      Krabbendam & Aleman's review (2003) of 12 controlled studies finds a weighted mean effect
      size (Cohen's d) of 0.45 with 95% CI, 0.26-0.64), which indicates a small to moderate effect
      of cognitive training (CT) for patients with schizophrenia.

      In Twamley et al.'s review (2003) of 17 randomised, controlled studies of CT, a weighted mean
      effect size was calculated across studies. The weighted mean effect sizes (Cohen's d) were
      0.32 in improvement in cognitive performance, 0.26 in reduction of symptom severity, and 0.51
      in the domain of everyday functioning. The review authors recommend longitudinal designs as
      well as the inclusion of real-life outcome measures in future trials.

      Many studies of CT have been underpowered (small sample sizes), which limits the conclusions
      that can be drawn from results of improvement (Ueland & Rund, 2005). The variability of
      outcome measures used also complicates interpretation of findings, thus, a consensus battery
      (MATRICS ) of outcome measures has been suggested for future studies. Silverstein & Wilkniss
      (2004) and Bellack (2004) note that the results of cognitive rehabilitation generally fail to
      secure the ecological validity, wherefore CT ought to be integrated in a broader psychosocial
      programme of intervention for schizophrenia. Other shortcomings in earlier studies include
      short-term programmes lacking sufficient long-sighted follow-up examinations as well as
      experimental designs lacking consideration of individual abilities and involvement. A recent
      review of cognitive rehabilitation (Velligan et al, 2006) underscores the importance of
      addressing motivation as a primary target.

      Hogarty et al's (2004) promising results from a randomised, controlled trial (N=121) of
      computer-assisted CT also highlight the importance of examining to what extent the control
      condition (psychosocial treatment) improve cognitive functioning. Broadly viewed, there is
      sufficient evidence that the combination of CT and psychosocial treatment, rather than
      individually appearing initiatives, have the greatest potential for promoting treatment
      outcome (Bell et al, 2003).

      There is a need for a well-organised and sufficiently large randomised clinical trial of the
      effect of integrated CT and psychosocial rehabilitation. In order to examine to what extent
      CT improves the psychosocial rehabilitation and facilitates new learning, one must identify
      and compare improvements on the level of neuropsychological performance as well as the level
      of everyday competencies (Reeder et al, 2006; Buchanan et al, 2005; McKibbin et al, 2004).
      The present trial employs a prospective design of 16 weeks with a following follow-up 10
      months after inclusion, and seeks in the CT to secure an individual adaptation and motivation
      trough continuous evaluations and level adjustments between patient and trainer.

      Objectives

        1. Primary hypothesis The effect of a 16-weeks programme of computer-based CT integrated in
           OPUS treatment on the patients' competencies in daily life is superior to standard OPUS
           treatment. Primary response variable: Total score on UPSA-B (Patterson et al, 2001
           Danish version).

        2. Secondary hypothesis The effect of a 16-weeks programme CT integrated in OPUS treatment
           on patients' cognitive functioning is superior to standard OPUS treatment. Response
           variables: Scores on MATRICS Consensus Cognitive Battery (MCCB), Trailmaking B and
           WCST-64 (computerized version).

        3. Tertiary hypothesis The effect of a 16-weeks programme of computer-based CT integrated
           in OPUS treatment is superior to standard OPUS treatment in terms of patients'
           association with the labour market, general health and self-esteem. Response variables:
           Occupational status and general functioning measures and Rosenberg's Self-Esteem Scale
           (Rosenberg, 1989).

      Furthermore, we want to examine the association between first episode patients' cognitive
      function level and competencies in daily life, can be divided in primary and secondary
      objectives:

      Blinding The instructor for CT will make a call with participants' data to CTU and thereafter
      inform the patients which intervention programme he or she has been allocated to. The study
      is not blinded in regard to patients, cognitive trainers and therapists. The blinding applies
      raters engaged with the outcome evaluation. In the follow-up the patient is instructed in
      advance not to reveal what type of treatment they have received. By registering which type of
      intervention the independent assessors of outcome believe the patient to be receiving it will
      be evaluated if blinding succeeded. The randomised intervention allocation is concealed until
      the statistical analyses of resulting data have been completed.

      Participants Patients are recruited from OPUS which is implemented as a standard treatment
      programme for young adults with firstepisode psychosis in Copenhagen and Århus. The staff in
      OPUS recruit patients to the project. The independent assessors interview referred patients
      and evaluate the following in- and exclusion criteria.

      Inclusion criteria 1) between 18 and 35 years of age, 2) first episode psychosis within F2
      spectrum or schizotypal disorder in ICD 10 - post-acute phase of illness, 3) sufficient
      comprehension of Danish, 4) written informed consent.

      Exclusion criteria

      1) rejection of participation, 2) organic disorder, 3) noticeable misuse of psychoactive
      drugs

      Control intervention group All patients receive the treatment usually provided in OPUS.

      Standard treatment in OPUS consists of affiliation with a primary contact person, involvement
      of family, possibility of psychoeducation and social skills training described in details at
      http://www.psykiatri.aaa.dk/cent_enh/opus.htm and www.opus-kbh.dk. Depending on individual
      needs patients are offered to take part in group therapy either social skills training (SST)
      or cognitive-behavioral therapy (CBT). Participation in SST or CBT might be beneficial for
      both cognition and everyday skills. To ensure comparability between the patients allocated to
      experimental intervention (CT) and the patients allocated to standard OPUS treatment, we
      stratify patients according to group therapy (SST/CBT) yes/no.

      Patients randomized to the control group will receive treatment as usual as described above.

      Experimental intervention A pilot study in OPUS Århus has led to the completion of a manual
      for a 16-week CT programme for patients with schizophrenia (Christensen & Olsen, 2006).

      One hour twice a week in 16 weeks patients engage in computer-assisted CT plus one competence
      dialog every other week. Training consists of four modules: the first three modules cover the
      areas of attention, memory and executive functions, and the last module focus on the
      cognitive area and related tasks that the individual patient need or prefer to work more on:
      Thus, the content of module 4 is based on both the patient's and the trainer's judgement.

      Training contains exercises of simple attention, attention span and vigilance, planning,
      problem solving, stimulus-bind and perseveration tendency, interaction-based training of
      working memory, and verbal and visual long-term memory. The CT approach is oriented towards
      teaching of compensatory strategies, but simple repetition of non-social cognitive tasks on a
      gradually increasing level of difficulty is also part of the CT program. By 90 % correct
      task-completion, the level is increased.

      Module 1 and 2 are based on computertasks (COGNIsoft), whereas the following modules 3 and 4
      include practical everyday tasks. In their review Twamley, Jeste and Bellack (2003) stress
      the importance of directly targeting everyday functioning of the patient. Thus,
      calendartraining is a vital part of this intervention: a way of addressing common
      difficulties of memory and planning ability. Calendartraining and competence dialogues both
      support environmental adaptation and transference of learning.

      Training relies on errorless learning principles, scaffolding, repetition, and
      strategy-learning as recommended by Wykes & van der Gaag (1999). Positive reinforcement,
      modelling, and verbal instructions are widely used. Trainers describe the structure and
      explain the purpose of training exercises at the beginning of every session to provide a
      consistent learning environment.

      Assessments All assessments except Present State Examination-interview (PSE, clinical
      version) and premorbid IQ (DART: Danish version of National Adult Reading Test, Nelson, 1991)
      are conducted at baseline, 4 months and 10 months after inclusion, irrespective of whether
      patients were following the full training programme (intention-to-treat principle).

        -  Positive and negative symptom evaluated with Positive and Negative Symptom Scale
           (PANSS).

        -  Assessment of health and occupational and general function.

        -  Neuropsychological testing of functional level in 7 cognitive domains. According to the
           NIMH-initiative the MATRICS Cognitive Consensus Battery (MCCB, Nuechterlein et al, 2004)
           includes seven separate cognitive areas. See table 1.

        -  Current level of competencies in 2 domains of daily life assessed using UCSD
           Performance-Based Skills Assessment (UPSA-B, Patterson et al, 2001, Danish version)

        -  Rosenberg's Self-Esteem Scale (Rosenberg, 1989 (1965), Danish version)

        -  Type and dose of antipsychotic medication (chlorpromazine equivalents).

      Table 1. Cognitive test battery.

      Domain of cognition: Tests:

        1. Speed of information processing BACS Symbol CodingCategory FluencyTrailmaking A

        2. Attention CPT-IP Identical Pairs

        3. Working memory Spatial SpanLetter-Number SpanTrailmaking B

        4. Verbal learning and memory Hopkins Verbal Learning Test-Revised

        5. Visuel learning and memory Brief Visuospatial Memory Test-Revised

        6. Problem-solving NAB MazesWisconsin Card Sorting Test, computerized version,64 cards

        7. Social cognition MSCEIT (Managing Emotions)

      Ethical considerations and informed consent The project has been approved by the Scientific
      Ethical Committees for Copenhagen and Frederiksberg and assigned case number (KF) 01 300017.
      The guidelines of The Danish Data Inspection and "clinicaltrials.gov" are followed. The
      interventions and methods of investigation involve no known physical or mental risks.
      Participation is voluntary and written informed consent is obtained. All patients are
      informed both verbally and in written form that they can withdraw from the trial at any time,
      without it having any consequences for their continued treatment.
    

Intervention name(s): Cognitive training
Intervention type(s): Behavioral
Intervention description(s): Cognitive training for 16 weeks integrated in OPUS psychosocial treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary purpose: Treatment