Improvement in mismatch negativity generation during d-serine treatment in schizophrenia: Correlation with symptoms
Abstract
Background Deficits in N-methyl-d-aspartate-type (NMDAR) function contribute to symptoms and cognitive dysfunction in schizophrenia. The efficacy of NMDAR agonists in the treatment of persistent symptoms of schizophrenia has been variable, potentially reflecting limitations in functional target engagement. We recently demonstrated significant improvement in auditory mismatch negativity (MMN) with once-weekly treatment with d-serine, a naturally occurring NMDAR glycine-site agonist. This study investigates effects of continuous (daily) NMDAR agonists in schizophrenia/schizoaffective disorder.Methods Primary analysis was on MMN after double-blind crossover (60mg/kg/d, n=16, 6weeks) treatment with d-serine/placebo. Secondary measures included clinical symptoms, neurocognition, and the effects of open-label (30-120mg/kg/d, n=21) d-serine and bitopertin/placebo (10mg, n=29), a glycine transport inhibitor.Results Double-blind d-serine treatment led to significant improvement in MMN frequency (p=0.001, d=2.3) generation and clinical symptoms (p=0.023, d=0.80). MMN frequency correlated significantly with change in symptoms (r=-0.63, p=0.002) following co-variation for treatment type. d-Serine treatment led to a significant, large effect size increase vs. placebo in evoked α-power in response to standards (p=0.036, d=0.81), appearing to normalize evoked α power relative to previous findings with controls. While similar results were seen with open-label d-serine, no significant effects of bitopertin were observed for symptoms or MMN.Conclusions These findings represent the first randomized double-blind placebo-controlled study with 60mg/kg d-serine in schizophrenia, and are consistent with meta-analyses showing significant effects of d-serine in schizophrenia. Results overall support suggest that MMN may have negative, as well as positive, predictive value in predicting efficacy of novel compounds.Clinical trials registration Clinicaltrials.gov: NCT00322023/NCT00817336 (d-serine); NCT01116830 (bitopertin).
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MMN is used as a biomarker for clinical trials.
“In addition, MMN is used as a biomarker for clinical trials (53, 54).”
From A Predictive Coding Perspective on Mismatch Negativity Impairment in Schizophrenia (2020) · cites this paper as [54]
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Kirihara, K., Tada, M., Koshiyama, D., Fujioka, M., Usui, K., Araki, T., & Kasai, K. (2020) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2020.00660 · Cited by 51 · see citing works
- Authors
- Kantrowitz, J. T., Epstein, M. L., Lee, M., Lehrfeld, N., Nolan, K. A., Shope, C., Petkova, E., Silipo, G., & Javitt, D. C.
- Affiliations
- Nathan Kline Institute for Psychiatric Research (US)
- The Graduate Center, CUNY (US)
- Corresponding author
- Kantrowitz, Joshua T.
- ORCID
- Venue
- Schizophrenia Research
- Publisher
- Elsevier BV
- Published
- 2018-01
- Volume
- 191
- Pages
- 70-79
- ISSN
- 0920-9964 (ISSN-L)
- OpenAlex
- W2596382174
- Cited by
- 123
- References
- 89
- Citations by year
- 2026: 4 · 2025: 12 · 2024: 15 · 2023: 17 · 2022: 13 · 2021: 16 · 2020: 16 · 2019: 13 · 2018: 10 · 2017: 7
- FWCI
- 10.33
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Schizophrenia Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- NIH (U01 MH074356, P50 MH086385)
- F. Hoffmann-La Roche
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Keywords
- D-serine, schizophrenia
- MeSH terms
- Acoustic Stimulation, Adolescent, Adult, Cognition Disorders, Contingent Negative Variation, Double-Blind Method, Evoked Potentials, Auditory, Female, Humans, Male, Middle Aged, Piperazines, Schizophrenia, Serine, Sulfones, Time Factors, Antipsychotic Agents, Meta-Analysis as Topic, Cross-Over Studies, Young Adult
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