Brain Imaging, Cognitive Enhancement and Early Schizophrenia
Condition: Schizophrenia; Schizoaffective Disorder
MeSH terms: Schizophrenia; Psychotic Disorders
Study type: Interventional

Summary: 
      The proposed project is designed to examine the effects of cognitive rehabilitation on brain
      structure and function in a randomized trial of 102 early course schizophrenia patients
      treated for 18 months with either cognitive enhancement therapy (CET) or an Enriched
      Supportive Therapy (EST) control, and then followed-up at 1-year post-treatment.
    

Detailed description: 
      Schizophrenia is a chronic and highly disabling disorder, making it imperative to apply
      interventions that alter its deleterious effects as early as possible. Impairments in
      neurocognition and social cognition, which appear to be linked to impaired structural and
      functional integrity in key brain regions, are the strongest predictors of functional
      disability in early course schizophrenia,making them key targets for early intervention.
      Although pharmacologic treatment of cognitive impairments is currently limited,our studies
      and others, including meta-analyses have shown that cognitive rehabilitation can be effective
      for addressing cognitive impairment in chronic patients. Most notably, Cognitive Enhancement
      Therapy (CET), a unique integrated approach to the rehabilitation of social and non-social
      cognitive impairments developed and tested by Hogarty and colleagues in our group, has shown
      substantial and lasting effects in chronic schizophrenia patients. Recently, the
      investigators have shown that the beneficial effects of CET can be successfully extended to
      those in the early phase of the disorder, resulting in large functional improvements.

      The investigators have posited that CET can be particularly effective as an early
      intervention strategy by capitalizing on a fronto-temporal plasticity reserve, and the
      investigators are now observing compelling, albeit preliminary evidence that CET can indeed
      slow the progression of gray matter loss in these very regions of the brain, which is
      associated with significantly improved cognition (see Preliminary Studies). Preserved
      structural integrity and improved brain function in fronto-temporal regions may be the
      critical mechanisms for supporting cognitive improvement in early course schizophrenia, yet
      remarkably little is known about the neurobiologic effects of cognitive rehabilitation, the
      durability of these effects post-treatment, and whether an initial fronto-temporal reserve
      portends a greater treatment response. Our exciting preliminary findings of the
      neuroprotective effects of CET represent the first study to demonstrate that the structural
      integrity of the brain in the early course of schizophrenia can be altered using cognitive
      rehabilitation. It is critical that these morphologic findings are examined with more
      advanced imaging techniques in larger samples to gain a precise understanding of the
      underlying neurobiologic mechanisms and predictors of cognitive and functional enhancement in
      early course schizophrenia. These goals are reflective of the strategic plan of NIMH to
      identify underlying neural mechanisms of mental disorders that can facilitate treatment, and
      personalize care to optimize treatment response. To accomplish this, the investigators
      propose to use comprehensive structural and functional imaging methods to study 102 new early
      course schizophrenia patients treated for 18 months in a randomized trial of CET or Enriched
      Supportive Therapy (EST) and: Aim #1: Confirm the neuroprotective effects of CET on
      fronto-temporal brain structure. Structural magnetic resonance imaging (MRI) assessments will
      be collected along with cognitive and functional outcome data at baseline, 9, and 18 months.
      It is hypothesized that patients treated with CET will demonstrate decreased loss of
      fronto-temporal gray matter relative to EST, and that this neuroprotection will be a
      mechanism of cognitive and functional improvement. Effects on other key brain regions will
      also be explored; Aim #2: Examine the effects of CET on fronto-temporal brain function.
      Functional MRI data using established executive and social cognition paradigms will be
      collected at baseline, 9, and 18 months along with cognitive and functional outcome data. It
      is hypothesized that CET patients will demonstrate enhanced fronto-temporal brain activity
      during these tasks relative to EST (see Section 3C.6.2 for specific predictions), and that
      this enhanced brain activity will be a mechanism of cognitive and functional improvement.
      Changes in fronto-temporal functional connectivity and their relations with improved brain
      structure and cognition will also be explored; and Aim #3: Examine the durability of CET
      effects on fronto-temporal brain structure and function, cognition, and functional outcome at
      1 year post-treatment. Identical neuroimaging, cognitive, and behavioral data will be
      collected as those assessed during active treatment. It is hypothesized that the differential
      neurobiologic benefits of CET relative to EST observed in Aims 1 and 2, and the cognitive and
      functional benefits of CET observed during active treatment will be sustained 1 year
      post-treatment.

      Exploratory Aim: Explore the effects of a fronto-temporal structural and functional reserve
      on CET treatment response. Moderator analyses will examine whether pre-treatment
      fronto-temporal structural and functional brain reserves (operationalized in Section 3C.8.2)
      predict larger cognitive and functional gains in CET. Exploratory analyses will also examine
      the degree to which later (18 mo) treatment improvement is dependent upon early (9 mo)
      neuroprotection and increased brain function, which may reflect plasticity.
    

Intervention name(s): Cognitive Enhancement Therapy; Enriched Supportive Therapy
Intervention type(s): Behavioral; Behavioral
Intervention description(s): Cognitive Enhancement Therapy (CET) consists of approximately 60 hours of computer-assisted neurocognitive training in attention, memory, and problem-solving; and 45 social-cognitive group sessions that employ in vivo learning experiences to foster the development of social wisdom and success in interpersonal interactions. CET begins with 3 months of weekly 1-hour neurocognitive training in attention, after which patients begin the weekly 1.5-hour social-cognitive groups. Neurocognitive training then proceeds concurrently with the socialcognitive groups.; Enriched Supportive Therapy is an individual approach that includes the established principles of supportive therapy previously tested by our group, which are "enriched" by selected practice principles from the effective Personal Therapy. These manualized supportive therapeutic practices include active listening, correct empathy, appropriate reassurance, basic psychoeducation, including computer-based educational programs, reinforcement of health-promoting initiatives, the provision of case management, and reliance on the advocacy and advice of the therapist in times of crisis.
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Care Provider)
Primary purpose: Treatment
Keywords: Early Course Schizophrenia; Cognitive Enhancement Therapy; Enriched Supportive Therapy