UC San Diego

Many patients with chronic psychotic disorders including schizophrenia (SZ) maintain meaningful levels of plasticity (i.e., capacity for change) within neurocognition-relevant brain mechanisms, as evidenced by gains in neurocognition and function after interventions such as targeted cognitive training. However, like many clinical features of these disorders, therapeutic responses in SZ are heterogeneous, and prospectively identifying treatment-sensitive individuals and individualized treatment modalities remains an unmet challenge. We propose that available plasticity in neurocognition-relevant brain mechanisms in individual SZ patients can be detected by gains in laboratory measures of early auditory information processing (EAIP) and auditory learning after a single challenge-dose of a pharmacologic agent; here, we present supportive data for this strategy with the non-competitive NMDA antagonist, memantine, and the psychostimulant, amphetamine. We describe a novel therapeutic model where this "challenge dose" strategy is used to prospectively identify a sensitive cohort of patients, and in these patients, a therapeutic response is elicited by pairing drug-enhanced EAIP and auditory learning with auditory-based targeted cognitive training.