Evidence map›Paper›PMID 36958998›Full record

Trial reportBiological psychiatry2023

Dose-Dependent Augmentation of Neuroplasticity-Based Auditory Learning in Schizophrenia: A Double-Blind, Placebo-Controlled, Randomized, Target Engagement Clinical Trial of the NMDA Glutamate Receptor Agonist d-serine.

Pejman Sehatpour, Dan V Iosifescu, Heloise M De Baun, Constance Shope, Megan R Mayer, James Gangwisch, Elisa Dias, Tarek Sobeih, Tse-Hwei Choo, Melanie M Wall and 6 more

Open access · greenAbstract readRandomized Controlled Trial
PubMed Full text at PMC Publisher
In one paragraph

Trial report in Biological psychiatry, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers, 2 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
24citing papers in PubMed, 2 pooled it
4.9field-weighted citation impact, top 4% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

24 citing papers in PubMed, 2 syntheses or guidelines pooled it, 33 citations in OpenAlex.

  1. Serotonin type 3 receptor (5-HTNeuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2026
    Pooled it
  2. Glutamatergic Modulation of Brain Function in Psychosis: A Systematic Review of Neuroimaging Studies.Biological psychiatry. Cognitive neuroscience and neuroimaging · 2025
    Pooled it
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4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

16 authors at 3 institutions in 1 country.

Pejman SehatpourArea Psychosis, New York State Psychiatric Institute, New York, New York; Psychiatry, College of Physicians and Surgeons, Columbia University, New York, New York; Nathan Kline Institute, Orangeburg, New York.
Dan V IosifescuNathan Kline Institute, Orangeburg, New York; Psychiatry, New York University Grossman School of Medicine, New York, New York.
Heloise M De BaunArea Psychosis, New York State Psychiatric Institute, New York, New York.
Constance ShopeNathan Kline Institute, Orangeburg, New York.
Megan R MayerArea Psychosis, New York State Psychiatric Institute, New York, New York.
James GangwischArea Psychosis, New York State Psychiatric Institute, New York, New York; Psychiatry, College of Physicians and Surgeons, Columbia University, New York, New York.
Elisa DiasNathan Kline Institute, Orangeburg, New York; Psychiatry, New York University Grossman School of Medicine, New York, New York.
Tarek SobeihNathan Kline Institute, Orangeburg, New York.
Tse-Hwei ChooArea Psychosis, New York State Psychiatric Institute, New York, New York; Psychiatry, College of Physicians and Surgeons, Columbia University, New York, New York.
Melanie M WallArea Psychosis, New York State Psychiatric Institute, New York, New York; Psychiatry, College of Physicians and Surgeons, Columbia University, New York, New York.
Alice MedaliaArea Psychosis, New York State Psychiatric Institute, New York, New York; Psychiatry, College of Physicians and Surgeons, Columbia University, New York, New York.
Alice M SapersteinPsychiatry, College of Physicians and Surgeons, Columbia University, New York, New York.
Lawrence S KegelesArea Psychosis, New York State Psychiatric Institute, New York, New York; Psychiatry, College of Physicians and Surgeons, Columbia University, New York, New York.
Ragy R GirgisArea Psychosis, New York State Psychiatric Institute, New York, New York; Psychiatry, College of Physicians and Surgeons, Columbia University, New York, New York.
Marlene CarlsonArea Psychosis, New York State Psychiatric Institute, New York, New York; Psychiatry, College of Physicians and Surgeons, Columbia University, New York, New York.
Joshua T KantrowitzArea Psychosis, New York State Psychiatric Institute, New York, New York; Psychiatry, College of Physicians and Surgeons, Columbia University, New York, New York; Nathan Kline Institute, Orangeburg, New York. Electronic address: jk3380@cumc.columbia.edu.
New York Psychoanalytic Society and Institute · USNathan Kline Institute for Psychiatric Research · USColumbia University · US

Funding

D-serine augmentation of neuroplasticity-based auditory learning in schizophreniaR33MH116093 · NIMH · NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC · PI KANTROWITZ, JOSHUA TOLKIEN · 2021 to 2023
$1.4M
D-serine augmentation of neuroplasticity-based auditory learning in schizophreniaR61MH116093 · NIMH · NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC · PI KANTROWITZ, JOSHUA TOLKIEN · 2019 to 2020
$1.2M
NIMH NIH HHS R33 MH116093NIMH NIH HHS R61 MH116093
6 · The paper itself

Abstract

backgroundPatients with schizophrenia show reduced NMDA glutamate receptor-dependent auditory plasticity, which is rate limiting for auditory cognitive remediation (AudRem). We evaluate the utility of behavioral and neurophysiological pharmacodynamic target engagement biomarkers, using a d-serine+AudRem combination.

methodsForty-five participants with schizophrenia or schizoaffective disorder were randomized to 3 once-weekly AudRem visits + double-blind d-serine (80, 100, or 120 mg/kg) or placebo in 3 dose cohorts of 12 d-serine and 3 placebo-treated participants each. In AudRem, participants indicated which paired tone was higher in pitch. The primary outcome was plasticity improvement, operationalized as change in pitch threshold between AudRem tones [(test tone Hz - reference tone Hz)/reference tone Hz] between the initial plateau pitch threshold (mean of trials 20-30 of treatment visit 1) to pitch threshold at the end of visit(s). Target engagement was assessed by electroencephalography outcomes, including mismatch negativity (pitch primary).

resultsThere was a significant overall treatment effect for plasticity improvement (p = .014). Plasticity improvement was largest within the 80 and 100 mg/kg groups (p < .001, d > 0.67), while 120 mg/kg and placebo-treated participants showed nonsignificant within-group changes. Plasticity improvement was seen after a single treatment and was sustained on subsequent treatments. Target engagement was demonstrated by significantly larger mismatch negativity (p = .049, d = 1.0) for the 100 mg/kg dose versus placebo.

conclusionsOur results demonstrate sufficient proof of principle for continued development of both the d-serine+AudRem combination and our target engagement methodology. The ultimate utility is dependent on the results of an ongoing larger, longer study of the combination for clinically relevant outcomes.

Indexed as

Antipsychotic AgentsSchizophreniaDouble-Blind MethodExcitatory Amino Acid AgonistsGlutamic AcidHumansNeuronal PlasticityN-MethylaspartateReceptors, N-Methyl-D-AspartateSerineAntipsychotic AgentsExcitatory Amino Acid AgonistsGlutamic AcidN-MethylaspartateReceptors, N-Methyl-D-AspartateSerineAuditory learningClinical trialMismatch negativityNMDA receptorSchizophreniaTarget engagement

Identifiers

PMID36958998
PMCPMC10313776
OpenAlexW4319999596

What OpenQuestion holds

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Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.