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
[Preprint]. 2023 May 19:rs.3.rs-2943290.
doi: 10.21203/rs.3.rs-2943290/v1.

Augmentation of learning in schizophrenia by D-serine is related to auditory and frontally-generated biomarkers: A randomized, double-blind, placebo-controlled study

Viraj Govani, Adithya Shastry, Daniel Iosifescu, Preetika Govil, Megan Mayer, Tarek Sobeih  1 , Tse Choo, Melanie Wall, Pejman Sehatpour, Joshua Kantrowitz  2
Affiliations

Augmentation of learning in schizophrenia by D-serine is related to auditory and frontally-generated biomarkers: A randomized, double-blind, placebo-controlled study

Viraj Govani et al. Res Sq. .

Update in

Abstract

Auditory cognition is impaired in schizophrenia, and typically engages a complex, distributed, hierarchical network, including both auditory and frontal input. We recently demonstrated proof of principle for the target engagement of an N-methyl-D-aspartate-type glutamate receptor (NMDAR) agonist + auditory targeted remediation (d-serine+AudRem) combination, showing significant improvement in auditory-learning induced plasticity and mismatch negativity. In this secondary analysis, we report on frontal EEG outcomes, assessing for both generalized effects and the mechanism of auditory plasticity. 21 schizophrenia or schizoaffective disorder participants were randomized to three 1x weekly AudRem + double-blind d-serine (100 mg/kg) visits. In AudRem, participants indicated which paired tone was higher in pitch. The focus of this secondary analysis was a frontally (premotor) mediated EEG outcome- event-related desynchronization in the b band (b-ERD), which was shown to be sensitive to AudRem in previous studies. d-Serine+AudRem led to significant improvement in b-ERD power across the retention and motor preparation intervals (F 1,18 =6.0, p=0.025) vs. AudRem alone. b-ERD was significantly related to baseline cognition, but not auditory-learning induced plasticity. The principal finding of this prespecified secondary analysis are that in addition to improving auditory based biomarkers, the d-serine+AudRem combination led to significant improvement in biomarkers thought to represent frontally mediated dysfunction, suggesting potential generalization of effects. Changes in auditory-learning induced plasticity were independent of these frontally mediated biomarkers. Ongoing work will assess whether d-serine+AudRem is sufficient to remediate cognition or whether targeting frontal NMDAR deficits with higher-level remediation may also be required. Trial Registration: NCT03711500.

PubMed Disclaimer

Conflict of interest statement

Dr. Kantrowitz reports having received consulting payments within the last 24 months from Alphasights, Putnam, techspert.io, Health Monitor, Third Bridge, MEDACorp, Trinity, Globaldata, GKA, Clearview, Clarivate, Health Advances, ECRI Institute, ExpertConnect, Slingshot, Antheum, Guidepoint, First Thought, Wedbush, Jefferies, Otsuka, Vox Neuro and Reckner. He has served on the MedinCell Psychiatry, Merck, Leal and the Karuna Advisory Boards. He has conducted clinical research supported by the NIMH, Sunovion, Roche, Cerevance, Click, Neurocrine, Corcept, Taisho and Boehringer Ingelheim within the last 24 months. He owns a small number of shares of common stock from GSK.

Dr. Iosifescu has received consulting honoraria from Alkermes, Allergan, Axsome, Biogen, Centers for Psychiatric Excellence, Jazz, Lundbeck, Otsuka, Precision Neuroscience, Sage, Sunovion; he has received research support (through his academic institutions) from Alkermes, Astra Zeneca, Brainsway, Litecure, Neosync, Otsuka, Roche, Shire.

Drs Sehatpour, Sobeih, Wall, and Mr. Govani, Shastry and Choo and and Ms. Mayer and Govil reported no biomedical financial interests or potential conflicts of interest.

Figures

Figure 1
Figure 1
Grand average ERP waveforms for d-serine and placebo during plasticity session.
Figure 2
Figure 2
Top: Time-frequency plots for baseline corrected single-trial power. The timing of S1 and S2 presentation, along with b-ERD power during the retention and motor preparation interval are as illustrated. q, a and b ranges are illustarted. Bottom: Bar graph of b-ERD power during the motor preparation interval, Inset shows topographical plots (headmaps) for b-ERD power at 1340 ms, midpoint of the motor preparation interval.
See this image and copyright information in PMC

References

    1. Kharawala S, Hastedt C, Podhorna J, Shukla H, Kappelhoff B, Harvey PD. The relationship between cognition and functioning in schizophrenia: A semi-systematic review. Schizophrenia research Cognition. 2022;27:100217. - PMC - PubMed
    1. Kantrowitz JT, Javitt DC. N-methyl-d-aspartate (NMDA) receptor dysfunction or dysregulation: the final common pathway on the road to schizophrenia? Brain Res Bull. 2010;83(3–4):108–21. - PMC - PubMed
    1. Fivel L, Mondino M, Brunelin J, Haesebaert F. Basic auditory processing and its relationship with symptoms in patients with schizophrenia: a systematic review. Psychiatry Research. 2023:115144. - PubMed
    1. Donde C, Kantrowitz JT, Medalia A, Saperstein AM, Balla A, Sehatpour P, et al. Early auditory processing dysfunction in schizophrenia: Mechanisms and implications. Neurosci Biobehav Rev. 2023;148:105098. - PMC - 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

Publication types

Associated data