Efficacy of Cognitive Remediation in Patients With Schizophrenia or Schizoaffective Disorder Stabilized on Lurasidone
Condition: Schizophrenia
MeSH terms: Schizophrenia; Psychotic Disorders
Study type: Interventional
Phase: Phase 3

Summary: 
      The investigators hypothesize that cognitive remediation will be superior to the active
      control group on the change from baseline to study end point of cognitive remediation phase
      on both co-primary outcome measures (standardized composite MATRICS score and Cognitive
      Assessment Interview).
    

Detailed description: 
      OVERVIEW & SPECIFIC AIMS Marked cognitive impairment underlies much of the social &
      occupational dysfunction associated with schizophrenia. Currently available antipsychotic
      medications are primarily effective in treating psychotic symptoms & have demonstrated only
      limited potential in ameliorating cognitive deficits in schizophrenia patients.

      Lurasidone is a novel compound synthesized by SEPRACOR, Inc.for the treatment of patients
      with schizophrenia & bipolar disorder. It possesses high affinity for dopamine D2, serotonin
      5-HT2A, 5-HT7, 5-HT1A & noradrenaline α2C receptors. Compared with other atypical
      antipsychotics, lurasidone demonstrates similar binding affinities for the D2 & 5-HT2A
      receptors, but greater affinity for serotonin 5-HT1A receptors. Lurasidone displays no
      affinity for histamine H1 or acetylcholine M1 receptors. In animal studies, lurasidone
      significantly reversed memory impairment induced by MK-801, an N-methyl-D-aspartate (NMDA)
      receptor antagonist, in a rat step-through type passive avoidance task. The maximum
      inhibitory effects of lurasidone were greater than those observed with risperidone,
      quetiapine, & olanzapine, while aripiprazole was not effective in reversing the impairment
      induced by MK-801. Additionally, lurasidone significantly reversed memory impairment induced
      by the anticholinergic drug scopolamine in the passive avoidance task. The reversal of
      pharmacologically induced cognitive deficits in rats by lurasidone is promising & warrants
      specific investigation in subjects with schizophrenia, given the prominence of cognitive
      deficits in this disorder.

      From a different therapeutic perspective, the utility of cognitive remediation in
      ameliorating cognitive deficits & improving functional outcomes in schizophrenia has recently
      been evaluated in several studies. A meta-analysis of these trials found effect sizes for
      improvement in cognitive & psychosocial functioning in the low to moderate range (McGurck
      2007). The best outcomes in psychosocial functioning were evident when cognitive remediation
      was combined with teaching of psychosocial skills.

      Given the recalcitrant nature of cognitive deficits in schizophrenia & their impact on
      functional capacity we felt that in designing a study to test the effectiveness of cognitive
      remediation we should maximize the likelihood of therapeutic benefit by administering
      cognitive remediation in the context of pharmacotherapy that may have potential for
      precognitive effects. By so doing we could possibly boost the effect sizes seen with
      cognitive remediation alone. In this study we will transition patients with schizophrenia (in
      whom a change in antipsychotic therapy is clinically warranted) from their current
      antipsychotic to lurasidone - clinicians will have eight weeks to complete the switch.
      Subjects who are successfully switched to lurasidone will then be randomized to receive
      either cognitive remediation or a non-specific mental activity control condition two
      times/week for a total of 30 sessions over a 4-6 month period. Our goal is to have 140
      patients complete the cognitive remediation phase.

      A subset of the sample will participate in 2 biomarker studies. Event related potentials &
      fMRI will be done in these subjects at baseline & study completion.

      This study will be done as an Investigator initiated trial (J. Lieberman, M.D. - PI) under a
      separate IND.

      Primary Aim: We hypothesize that cognitive remediation will be superior to the active control
      group on the change from baseline to study end point of cognitive remediation phase on both
      co-primary outcome measures (standardized composite MATRICS score & Cognitive Assessment
      Interview).

      Additional aims

        1. To compare cognitive remediation to active control on functional outcome as assessed by
           the change in UCSD Performance-Based Skills Assessment (UPSA-Brief) from baseline to end
           point of cognitive remediation phase.

        2. To compare cognitive remediation to active control on changes from lurasidone stabilized
           baseline to end point in indices of functional brain activation (ERP & fMRI) during
           cognitive activation tasks.

        3. Evaluate the effect of 8 weeks of lurasidone treatment on cognitive & functional
           outcomes as assessed by changes from baseline in the MATRICS composite score, CAI, &
           UPSA-Brief.

        4. Evaluate the effect of cognitive remediation compared to nonspecific mental activity on
           cognitive & functional outcomes as assessed by changes from lurasidone stabilized
           baseline to end of cognitive remediation phase in the MATRICS composite score, CAI, &
           UPSA-Brief.

        5. Evaluate the efficacy, safety, & tolerability of lurasidone in patients with
           schizophrenia as assessed by the change from baseline to week 8 & to end of cognitive
           remediation phase in the PANSS total score, Side Effect Checklist, AIMS, SAS, BAS, &
           frequency of abnormal laboratory values.
    

Intervention name(s): Cognitive Remediation
Intervention type(s): Drug
Intervention description(s): Cognitive remediation intervention will be administered in small group settings twice weekly for 30 sessions and will utilize computerized and verbal group training exercises to address basic skills such as auditory processing, attention, processing speed, and verbal working memory and learning, as well as intermediate and complex skills such as deductive reasoning, planning and sequencing, set shifting, and complex problem solving.
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary purpose: Treatment
Keywords: Cognition; Function; Attention; Vigilance; Verbal Memory; Visual Memory; Processing Speed; Problem Solving; Social Cognition