MH94320 seeks 3 years of renewed support to test the effects of the NMDA antagonist, memantine (MEM), on auditory processing in patients with schizophrenia (SZ). Studies in FY 1-4 produced the surprising and unprecedented findings that a single pill of MEM (20 mg) significantly enhanced (made ?more normal?) 3 measures of aberrant early auditory information processing (EAIP) in SZ patients: prepulse inhibition (PPI), mismatch negativity (MMN) and gamma auditory steady-state response (ASSR). Based on structural equation modeling evidence that EAIP is a root cause of functional impairment in SZ, a drug-induced improvement in EAIP is a compelling neurobiological signal that MEM is accessing brain mechanisms that ultimately will provide a pathway to therapeutics. However, acute gains in EAIP are insufficient to enhance neurocognition in SZ. This renewal application tests the impact of MEM on functional measures of auditory processing fidelity (APF) and auditory learning in SZ patients and matched healthy subjects (HS), to identify ?intermediate phenotypes?, bridging immediate MEM-enhanced EAIP with eventual gains in neurocognition and function. Such findings would implicate mechanisms connecting neurophysiological measures of EAIP to the neurocognitive and functional outcomes that they generate, and would identify candidate biomarkers predicting a therapeutic response to MEM, paired with Targeted Cognitive Training (TCT), in future clinical trials. While current medications for SZ do not significantly enhance functional outcome, some forms of auditory-based TCT effectively reduce symptoms and improve function in SZ. One premise of this application is that benefits of TCT in SZ will be enhanced by drugs that increase specific cognitive abilities, including auditory processing. While the clinical impact of MEM in SZ is controversial, no studies have tried to utilize MEM's positive effects on EAIP to augment the benefits of TCT. We propose to test a mechanistic rationale for a future trial of ?Pharmacologic Augmentation of Cognitive Training? (PACT) with MEM, in which MEM- enhanced EAIP improves neurocognition and function in SZ patients via gains in APF and/or auditory learning. In 3 years, MH94320 will test the prediction that MEM (20 mg p.o.) will acutely enhance functional measures of APF and learning as well as EAIP in 41 SZ patients and 41 HS, via a double-blind, placebo- controlled cross-over design (Aim 1). Regional sources of MEM-enhanced EAIP will be localized. Predictors of MEM sensitivity will be assessed, including baseline performance, and specific SNPs in glutamate receptor genes previously associated with MEM sensitivity. Path Analyses will determine if MEM-enhanced EAIP leads to improved APF/learning, thus establishing a specific pathway to therapeutic enhancement of cognition and function (Aims 2-3). Findings will guide future efforts by explicating mechanisms by which MEM-enhanced EAIP produces gains in neurocognition and function, and by identifying ?personalized? biomarkers of MEM sensitivity as well as candidate physiological signals of target engagement for a future R61/R33 application.

Public Health Relevance

Laboratory measures of early auditory information processing (EAIP) are impaired in patients with schizophrenia, and are also strongly associated with neurocognition and level of life function. We demonstrated that the neuroprotective drug, memantine, significantly enhances (makes ?more normal?) these EAIP measures in schizophrenia patients tested 3-6 hours later, and the present application will determine whether this enhanced EAIP activity is accompanied by improvements in higher-order measures of auditory processing. If so, such changes would provide a strong rationale for testing the potential benefits of memantine to auditory-based cognitive training in schizophrenia, and would suggest both a mechanism for such benefits as well as a set of biomarkers predicting sensitivity to such benefits in individual schizophrenia patients.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
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Hillefors, MI
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University of California, San Diego
Schools of Medicine
La Jolla
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Swerdlow, Neal R; Light, Gregory A (2018) Sensorimotor gating deficits in schizophrenia: Advancing our understanding of the phenotype, its neural circuitry and genetic substrates. Schizophr Res 198:1-5
Huang, L; Shum, E Y; Jones, S H et al. (2018) A Upf3b-mutant mouse model with behavioral and neurogenesis defects. Mol Psychiatry 23:1773-1786
Kantrowitz, Joshua T; Swerdlow, Neal R; Dunn, Walter et al. (2018) Auditory System Target Engagement During Plasticity-Based Interventions in Schizophrenia: A Focus on Modulation of N-Methyl-D-Aspartate-Type Glutamate Receptor Function. Biol Psychiatry Cogn Neurosci Neuroimaging 3:581-590
Swerdlow, Neal R; Bhakta, Savita G; Light, Gregory A (2018) Room to move: Plasticity in early auditory information processing and auditory learning in schizophrenia revealed by acute pharmacological challenge. Schizophr Res 199:285-291
Light, Gregory A; Zhang, Wen; Joshi, Yash B et al. (2017) Single-Dose Memantine Improves Cortical Oscillatory Response Dynamics in Patients with Schizophrenia. Neuropsychopharmacology 42:2633-2639
Swerdlow, Neal R; Bhakta, Savita G; Rana, Brinda K et al. (2017) Sensorimotor gating in healthy adults tested over a 15 year period. Biol Psychol 123:177-186
Swerdlow, Neal R; Tarasenko, Melissa; Bhakta, Savita G et al. (2017) Amphetamine Enhances Gains in Auditory Discrimination Training in Adult Schizophrenia Patients. Schizophr Bull 43:872-880
Swerdlow, Neal R; Braff, David L; Geyer, Mark A (2016) Sensorimotor gating of the startle reflex: what we said 25 years ago, what has happened since then, and what comes next. J Psychopharmacol 30:1072-1081
Tarasenko, Melissa; Perez, Veronica B; Pianka, Sean T et al. (2016) Measuring the capacity for auditory system plasticity: An examination of performance gains during initial exposure to auditory-targeted cognitive training in schizophrenia. Schizophr Res 172:123-30
Swerdlow, Neal R; Bhakta, Savita; Chou, Hsun-Hua et al. (2016) Memantine Effects On Sensorimotor Gating and Mismatch Negativity in Patients with Chronic Psychosis. Neuropsychopharmacology 41:419-30

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