Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2020;5(4):e200018.
Epub 2020 Aug 6.

Grant Report on d-Serine Augmentation of Neuroplasticity-Based Auditory Learning in Schizophrenia

Affiliations

Grant Report on d-Serine Augmentation of Neuroplasticity-Based Auditory Learning in Schizophrenia

Natalie de la Garrigue et al. J Psychiatr Brain Sci. 2020.

Abstract

We report on the rationale and design of an ongoing NIMH sponsored R61-R33 project in schizophrenia/schizoaffective disorder. This project studies augmenting the efficacy of auditory neuroplasticity cognitive remediation (AudRem) with d-serine, an N-methyl-d-aspartate-type glutamate receptor (NMDAR) glycine-site agonist. We operationalize improved (smaller) thresholds in pitch (frequency) between successive auditory stimuli after AudRem as improved plasticity, and mismatch negativity (MMN) and auditory θ as measures of functional target engagement of both NMDAR agonism and plasticity. Previous studies showed that AudRem alone produces significant, but small cognitive improvements, while d-serine alone improves symptoms and MMN. However, the strongest results for plasticity outcomes (improved pitch thresholds, auditory MMN and θ) were found when combining d-serine and AudRem. AudRem improvements correlated with reading and other auditory cognitive tasks, suggesting plasticity improvements are predictive of functionally relevant outcomes. While d-serine appears to be efficacious for acute AudRem enhancement, the optimal dose remains an open question, as does the ability of combined d-serine + AudRem to produce sustained improvement. In the ongoing R61, 45 schizophrenia patients will be randomized to receive three placebo-controlled, double-blind d-serine + AudRem sessions across three separate 15 subject dose cohorts (80/100/120 mg/kg). Successful completion of the R61 is defined by ≥moderate effect size changes in target engagement and correlation with function, without safety issues. During the three-year R33, we will assess the sustained effects of d-serine + AudRem. In addition to testing a potentially viable treatment, this project will develop a methodology to assess the efficacy of novel NMDAR modulators, using d-serine as a "gold-standard".

Keywords: N-methyl-d-aspartate-type glutamate receptor; auditory remediation; auditory theta; cognition; mismatch negativity; schizophrenia.

PubMed Disclaimer

Conflict of interest statement

CONFLICTS OF INTEREST The authors declare that they have no conflicts of interest associated with this project.

Figures

Figure 1.
Figure 1.
Schematic of model of auditory plasticity in schizophrenia. We show an auditory cortex pyramidal cell receiving bottom-up input from the thalamic medial geniculate nucleus (MGN), parvalbumin (PV), and somatostatin (SST) interneurons, which in-turn receive top-down input from posterior parietal or frontoparietal neurons (inset), thus interacting with dorsal attention and frontoparietal control nodes/networks. NMDAR, noted by the red “*” appear to be involved at multiple levels. Adapted from [15] with permission copyright © 2016 Oxford University Press (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article).
Figure 2.
Figure 2.
Voltage topography maps for mismatch negativity (MMN) for indicated group for Baseline (left) and Final (right) shown at peak latencies for intermittent (A) and sustained (B) treatment. Analyzed electrode noted by red circles. Analyzed electrode noted by red circles (Fz). (C) Scatter plot for % change in behavioral plasticity during AudRem vs change in MMN amplitude. Modified from [15,124]. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
Figure 3.
Figure 3.
Study Flow Chart. *Three 15-subject cohorts will be conducted sequentially, beginning with a d-Serine dose of 80 mg, followed by a 100 and 120 mg/kg cohort. A 60 mg/kg cohort will be added in case of safety concern in 80 or 100 mg/kg cohort.

References

    1. McCleery A, Green MF, Hellemann GS, Baade LE, Gold JM, Keefe RS, et al. Latent structure of cognition in schizophrenia: a confirmatory factor analysis of the MATRICS Consensus Cognitive Battery (MCCB). Psychol Med. 2015;45(12):2657–66. - PMC - PubMed
    1. Keefe RS, Harvey PD. Cognitive impairment in schizophrenia. Handb Exp Pharmacol. 2012(213):11–37. - PubMed
    1. Kern RS, Gold JM, Dickinson D, Green MF, Nuechterlein KH, Baade LE, et al. The MCCB impairment profile for schizophrenia outpatients: results from the MATRICS psychometric and standardization study. Schizophr Res. 2011;126(1–3):124–31. - PMC - PubMed
    1. Keefe RS, Fox KH, Harvey PD, Cucchiaro J, Siu C, Loebel A. Characteristics of the MATRICS Consensus Cognitive Battery in a 29-site antipsychotic schizophrenia clinical trial. Schizophr Res. 2011;125(2–3):161–8. - PubMed
    1. Jonsson CO, Sjostedt A. Auditory perception in schizophrenia: a second study of the Intonation test. Acta Psychiatr Scand. 1973;49(5):588–600. - PubMed

LinkOut - more resources