Pharmacologic augmentation of targeted cognitive training in schizophrenia

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In response to RFA-MH-18-705, this application develops a novel treatment strategy for chronic psychotic disorders, via Pharmacologic Augmentation of Cognitive Therapies (PACTs), and thereby directly addresses a critical need for more effective treatments for these devastating brain disorders. Despite 60 years as the major therapeutic tool for chronic psychotic disorders, including schizophrenia, antipsychotics may not significantly alter the course or real-life functional impact of these disorders. Modest clinical benefits in these patients can be achieved via specific cognitive therapies (CTs), including “bottom-up” sensory-based targeted cognitive training (TCT), but such treatments are time- and resource-intensive, and responses are incomplete and variable. This application seeks a practical way to augment the benefits of TCT in schizophrenia patients. We hypothesize that specific pro-cognitive agents will augment the clinical gains from TCT in schizophrenia patients, and that this PACT approach will be particularly effective in biomarker-defined subgroups of patients. Preliminary support for this hypothesis comes from the PI's studies (MH59803): in antipsychotic-medicated schizophrenia patients, the pro-attention drug, d-amphetamine, significantly enhanced learning in an auditory discrimination task (Posit Science “Sound Sweeps”). “Sound Sweeps” is a key component of a TCT program known to produce clinical gains in schizophrenia patients. Amphetamine- enhanced gains in auditory processing speed (APS) learning in schizophrenia patients were associated with baseline (pre-drug) levels of specific neurophysiological biomarkers. Dose-response and time course studies identified optimal amphetamine dose (5 mg po) and time (1 h pre-TCT) for maximal pro-learning effects. Consistent with a large literature, amphetamine was safe and well tolerated in this patient population. This application conducts a careful assessment of this PACT strategy for schizophrenia in 3 Aims: Aim 1) Confirmation of target engagement: 54 well-characterized schizophrenia patients will be tested to confirm that amphetamine (5 mg po) enhances APS learning; Aim 2) Efficient pilot testing: Subjects from Aim 1 are randomized into 2 treatment arms (n=27/arm) for a double-blind PBO-controlled 30-session clinical trial of amphetamine+TCT vs. PBO+TCT, to determine whether amphetamine augments the magnitude, rate and/or durability of TCT-induced gains, and whether these gains are associated with target engagement, using specific Go/No-Go criteria and outcome measures of symptoms, neurocognition and real-life function; Aim 3) Identify biomarker predictors of the PACT response, based on neurocognitive, electrophysiological, psychophysiological and performance-based measures assessed pre- and post-TCT. This is a highly novel, high-risk high-reward application to develop a novel treatment paradigm and thereby relieve suffering in patients with chronic psychotic disorders.