This R01 will establish the biological basis for a novel treatment strategy for schizophrenia (SZ), by identifying biomarkers that predict pro-cognitive drug effects in SZ patients. These pro-cognitive effects would be utilized to specifically enhance the clinical impact of cognitive therapies (CTs) for SZ;similar strategies are being effectively advanced for the treatment of anxiety disorders. This application will test the effects of a """"""""challenge dose"""""""" of the low-affinity NMDA antagonist, memantine (MEM), on sensorimotor gating and neuro- cognition in SZ patients;specific hypotheses will be tested in relation to the moderating impact of physiological and genetic biomarkers on these MEM effects. Predictors of positive effects of MEM will be used to identify enriched """"""""MEM-sensitive"""""""" SZ patient cohorts for trials using MEM to augment the therapeutic effects of CTs. The pharmacotherapy of SZ has been dominated by drugs with limited clinical impact. Some forms of CTs, including the broader formats of cognitive rehabilitation and cognitive training, effectively reduce symptoms and improve function in SZ. The premise of this application is that the benefits of CTs in SZ might be enhanced by drugs that increase specific cognitive abilities, including working memory (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 pro-cognitive agents to biomarker-identified sensitive patients. We recently reported that a single dose of the safe, neuroprotective, widely used Alzheimer's disease medication, MEM (20 mg p.o.), significantly increased prepulse inhibition (PPI) of startle in healthy subjects. These PPI-enhancing effects of MEM are associated with: 1) increased WM;and 2) phenotypes linked to the high activity Val158Met COMT polymorphism. PPI is 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, we will detect MEM-associated increases in PPI and WM, particularly among Val/Val patients. We 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 will assess the acute effects of MEM (0 vs. 10 or 0 vs. 20 mg p.o.) in 80 SZ patients and 80 healthy subjects, 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. Findings from this study will guide future clinical trials testing the overall effectiveness of MEM as an adjunct to CT by identifying biomarker-defined patients most likely to benefit from this therapeutic regimen;the feasibility of such trials is now being tested by the PI's R34 MH093453.

Public Health Relevance

Cognitive therapies are moderately effective at reducing symptoms and improving life function in schizophrenia patients. The present application aims to develop a strategy for increasing the effectiveness of cognitive therapies in schizophrenia through the use of pro-cognitive medications. Specific biomarkers will be studied that identify patients most sensitive to these pro-cognitive medications, based on suggestive findings in healthy controls, with the future aim of using these biomarkers in a large clinical trial of medication-enhanced cognitive interventions in schizophrenia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH094320-03
Application #
8666056
Study Section
Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
Program Officer
Hillefors, MI
Project Start
2012-06-08
Project End
2016-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Psychiatry
Type
Schools of Medicine
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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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