Biomarker Strategies for Medication-Enhanced Cognitive Training in Schizophrenia
Condition: Schizophrenia
MeSH terms: Schizophrenia
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      Cognitive training is moderately effective at reducing symptoms and improving life function
      in schizophrenia patients. The present application develops a strategy for increasing the
      effectiveness of cognitive training through the use of pro-cognitive medications. Specific
      biomarkers will be studied that identify patients most sensitive to these pro-cognitive
      medications, to test the feasibility of using these biomarkers in a large clinical trial of
      medication-enhanced cognitive training in schizophrenia.
    

Detailed description: 
      This R34 application responds to PAR-09-173, to achieve the first goal of this FOA by
      supporting: "the development and/or pilot testing of new or adapted interventions." The two
      overarching goals of this application are: 1) to test the effects of the acute administration
      of the NMDA antagonist, memantine (MEM), on sensorimotor gating and working memory (WM) in
      schizophrenia (SZ) patients, and 2) to assess the feasibility of using MEM to predictably
      enhance the therapeutic benefits of cognitive training in SZ.

      The pharmacotherapy of SZ has been dominated by antidopaminergic drugs with limited clinical
      impact. Some forms of psychosocial rehabilitation, such as cognitive training (CT), appear to
      effectively reduce symptoms and improve function in SZ. The premise of this application is
      that the benefits of CT in SZ might be enhanced by drugs that increase specific cognitive
      abilities, including WM, even if these pro-cognitive drugs lack clinical impact when
      administered without CT. The main goal of this application is to develop an innovative
      intervention strategy that enhances the clinical benefits of CT in SZ through administration
      of a pro-cognitive agent to biomarker-identified sensitive patients.

      The investigators reported that a single dose of the widely used Alzheimer's disease
      medication, MEM (20 mg p.o.), significantly increased prepulse inhibition (PPI) of the
      startle reflex in healthy subjects. PPI-enhancing effects of MEM in healthy subjects are
      associated with: 1) increased WM; and 2) phenotypes linked to the high activity Val158Met
      COMT polymorphism. PPI is consistently impaired in SZ patients; lowest levels of PPI in
      patients are associated with: 1) poor functional outcome; and 2) the Val/Val COMT genotype.
      If our MEM findings in healthy subjects are reproduced in SZ patients, the investigators will
      detect MEM-associated improvements in PPI and WM, particularly among Val/Val patients. The
      investigators will then be positioned to test the hypothesis that acute PPI and WM-enhancing
      effects of MEM predict therapeutic benefit of MEM in SZ patients undergoing CT.

      This application has two aims: Aim 1 will assess the acute effects of MEM (0 vs. 10 or 0 vs.
      20 mg p.o.) in 60 SZ patients, to test the prediction that MEM will increase PPI and enhance
      WM in SZ patients, particularly in those characterized by low basal PPI levels and/or the
      Val/Val COMT genotype. Mismatch negativity and gamma band synchronization will also be
      assessed as potentially informative MEM-sensitive and functionally relevant biomarkers. Aim 2
      will assess the feasibility of testing the therapeutic benefit of MEM as an adjunct to CT in
      SZ patients, and the feasibility of testing the primary hypothesis that such benefit will be
      predicted by increased PPI and/or WM in SZ patients after the Aim 1 single dose MEM
      challenge. It is predicted that subject recruitment and completion in both arms of a
      controlled 12-week CT trial in SZ out-patients among subjects completing Aim 1 will be
      appropriate for testing both the overall effectiveness of MEM as an adjunct to CT and the
      ability to predict this effectiveness among biomarker-identified patient subgroups.
    

Intervention name(s): Memantine; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Each participant receives a single pill of placebo or active drug (memantine, 10 or 20 mg) and completes about 6 hours of testing in the laboratory. One week later, that participant receives a single pill of the alternate comparator and is again tested in the laboratory. Thus, in total, each participant receives one placebo pill and one active pill, separated by one week.; Each participant receives a single pill of placebo or active drug (memantine, 10 or 20 mg) and completes about 6 hours of testing in the laboratory. One week later, that participant receives a single pill of the alternate comparator and is again tested in the laboratory. Thus, in total, each participant receives one placebo pill and one active pill, separated by one week.
Other intervention name(s): Namenda
Intervention MeSH terms: Memantine
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Health Services Research
Keywords: Schizophrenia; prepulse inhibition; neurocognition; working memory; memantine; MATRICS Consensus Cognitive Battery