Biomarker Strategies for Medication-Enhanced Cognitive Training in Schizophrenia

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.

Inclusion Criteria:

- A diagnosis of schizophrenia or schizoaffective disorder - depressed type

Exclusion Criteria:

- Age range,

- Current alcohol or drug abuse