Memantine augmentation of cognitive training in schizophrenia

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In response to RFA-MH-18-705, this application develops and tests a novel treatment strategy for improving cognition in patients with schizophrenia (SZ), via Pharmacologic Augmentation of Cognitive Therapies (PACTs), and directly addresses a critical need for more effective treatments for these disabling impairments. Cognitive benefits in SZ patients can be achieved via “bottom-up” sensory-based targeted cognitive training (TCT) therapies, but such treatments are time- and resource-intensive, and responses are incomplete and variable. This application tests a rational and empirically supported platform for augmenting the benefits of TCT in antipsychotic medicated SZ patients by adjunctive daily treatment of 20 mg memantine (MEM), an FDA approved medication for the treatment of cognitive dysfunction in Alzheimer's Disease. Recent meta-analyses of MEM augmentation in antipsychotic-medicated SZ patients have demonstrated its safety, tolerability, and effectiveness at improving scores on brief cognitive screening tests. We hypothesize that MEM will augment TCT learning and hence the clinical gains from TCT, and that this PACT approach will be most effective in biomarker-defined subgroups of patients. Preliminary support for these hypotheses comes from our proof-of-concept, randomized, controlled studies of single-dose exposure to MEM relative to placebo. In these studies, we found that MEM significantly enhanced learning in auditory discrimination, the key component of the TCT program which is known to drive the cognitive gains in SZ patients following 30-50h of TCT. We also found that a single dose of MEM significantly enhanced several biomarkers of early sensory information processing in antipsychotic medicated SZ patients. Dose-response and time course studies identified the optimal MEM dose (20 mg) for maximal pro-learning effects. This application conducts a careful assessment of this PACT strategy for SZ: Aim 1) Confirmation of target engagement: 54 SZ patients will be tested to confirm that MEM (20 mg) enhances measures of TCT learning; Aim 2) Efficient pilot testing: Subjects from Aim 1 will be randomized into 2 treatment arms (n=27/arm) for a double-blind placebo-controlled 30-session clinical trial of MEM+TCT vs. placebo+TCT, to determine whether daily dosing of MEM augments the magnitude, rate and/or durability of TCT gains, and whether these gains are associated with target engagement, using specific Go/No-Go criteria and outcome measures of symptoms, cognition and real-life function; Aim 3) Predictive biomarker identification of the PACT response, based on cognitive, electrophysiological, and performance-based measures assessed pre- and post-TCT. This is a highly novel, high-risk high-reward application to develop a PACT-based treatment paradigm that will enhance cognition, improve recovery and enhance outcomes for patients with schizophrenia, and will determine whether a future, fully-powered “Confirmatory Efficacy trial” of this approach is warranted.