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D-serine for the treatment of negative symptoms in individuals at clinical high risk of schizophrenia: a pilot, double-blind, placebo-controlled, randomised parallel group mechanistic proof-of-concept trial
Abstract
Background Antagonists of N-methyl-D-aspartate-type glutamate receptors (NMDAR) induce symptoms that closely resemble those of schizophrenia, including negative symptoms. D-serine is a naturally occurring NMDAR modulator that reverses the effects of NMDAR antagonists in animal models of schizophrenia. D-serine effects have been assessed previously for treatment of established schizophrenia, but not in the early stages of the disorder. We aimed to assess effects of D-serine on negative symptoms in at risk individuals.Methods We did a double-blind, placebo-controlled, parallel-group randomised clinical trial at four academic US centres. Individuals were eligible for inclusion in the study if they were at clinical high risk of schizophrenia, aged between 13-35 years, had a total score of more than 20 on the Scale of Prodromal Symptoms (SOPS), and had an interest in participation in the clinical trial. Exclusion criteria included a history of suprathreshold psychosis symptoms (ie, no longer qualifying as prodromal) or clinical judgment that the reported symptoms from the SOPS were accounted for better by another disorder (eg, depression). Randomisation was done using a generated list with block sizes of four. Participants were stratified by site, with participants, investigators, and assessors all masked through use of identical looking placebos and centralised drug dispensation to study assignment. D-serine (60 mg/kg) was given orally in divided daily doses for 16 weeks. The primary endpoint was for negative SOPS, measured weekly for the first 6 weeks, then every 2 weeks. Participants who received at least one post-baseline assessment were included in analysis. Serum cytokine concentrations were collected at baseline, midpoint, and endpoint to assess the mechanism of action. Safety outcomes including laboratory assessments were obtained for all individuals. This trial is registered with ClinicalTrials.gov, number NCT0082620.Findings We enrolled participants between April 2, 2009, and July 23, 2012. 44 participants were randomly assigned to receive either D-serine (n=20) or placebo (n=24); 35 had assessable data (15 D-serine, 20 placebo). D-serine induced a 35·7% (SD 17·8) improvement in negative symptoms, which was significant compared with placebo (mean final SOPS negative score 7·6 [SEM 1·4] for D-serine group vs 11·3 [1·2] for placebo group; d=0·68, p=0·03). Five participants who received D-serine and nine participants who received placebo discontinued the study early because of withdrawn consent or loss to follow-up (n=8), conversion to psychosis (n=2), laboratory-confirmed adverse events (n=2), or protocol deviations (n=2).Interpretation This study supports use of NMDAR-based interventions, such as D-serine, for treatment of prodromal symptoms of schizophrenia. On the basis of observed effect sizes, future studies with sample sizes of about 40 per treatment group would be needed for confirmation of beneficial effects on symptoms and NMDAR-related inflammatory changes. Long-term studies are needed to assess effects on psychosis conversion in individuals at clinical high risk of schizophrenia.Funding National Institutes of Health.
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“Published studies have revealed beneficial effects in schizophrenia patients as an add-on to maintenance medication [100][101][102][103] and ongoing studies are following up their results and including additional metrics of efficacy such as brain GSH imaging in order to reflect the BBB permeability analyses of NAC that have been performed in rodents 104 .”
From Linking early-life NMDAR hypofunction and oxidative stress in schizophrenia pathogenesis (2016) · cites this paper as [100]
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Metadata
- Authors
- Kantrowitz, J. T., Woods, S. W., Petkova, E., Cornblatt, B., Corcoran, C. M., Chen, H., Silipo, G., & Javitt, D. C.
- Affiliations
- Nathan Kline Institute for Psychiatric Research (US)
- Yale University (US)
- Zucker Hillside Hospital (US)
- Columbia University (US)
- University of Florida (US)
- Corresponding author
- Javitt, Daniel C
- ORCID
- Venue
- The Lancet Psychiatry
- Publisher
- Elsevier BV
- Published
- 2015-05
- Volume
- 2
- Issue
- 5
- Pages
- 403-412
- ISSN
- 2215-0366 (ISSN-L)
- OpenAlex
- W2070856797
- Cited by
- 148
- References
- 62
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 7 · 2023: 7 · 2022: 11 · 2021: 19 · 2020: 15 · 2019: 19 · 2018: 17 · 2017: 16 · 2016: 20 · 2015: 4
- FWCI
- 15.41
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Lancet Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (UL1 TR000040)
- National Center for Advancing Translational Sciences
- 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
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Keywords
- D-serine, negative symptoms, schizophrenia, clinical high risk, prodromal psychosis, NMDA receptor modulation, serum cytokines, mechanism of action, early intervention
- MeSH terms
- Adolescent, Adult, Double-Blind Method, Female, Humans, Male, Schizophrenia, Serine, Receptors, N-Methyl-D-Aspartate, Treatment Outcome, Risk Assessment, Young Adult
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