D-serine Augmentation of Neuroplasticity

NCT03711500 | Completed Phase 1 Results DMC FDA Drug

• 1 other identifier: 7725
• Study Type: interventional
• Target: 45
• Locations: 1 country
• Sites: 2

Brief Summary

Schizophrenia is a major public health problem associated with cognitive deficits, such as short and long term memory, executive functioning, attention and speed of processing that are amongst the strongest predictors of impaired functional outcome. In addition, schizophrenia patients show reduced "plasticity", defined as reduced learning. D-serine is a naturally occurring activator of the N-methyl-d-aspartate-type glutamate receptors (NMDAR) in the brain, and this project will assess the optimal dose of D-serine treatment over three sessions of a program designed to measure auditory plasticity.

Conditions

Schizophrenia; Schizo Affective Disorder

Keywords

plasticity

Outcome Measures

Primary Outcomes (4)

• Plasticity Improvement (Change in Tone Matching Threshold)

  Participants underwent three treatment sessions, 1x week. This is the outcome of the auditory remediation. In Auditory Remediation, participants are presented with paired tones (e.g. Stimulus 1 ("reference") and Stimulus 2 ("test"): S1 and S2) and indicate which tone is higher in pitch (frequency). In the first pair, the ratio is 50% (e.g. 1000±500 Hz). A two-down/one-up staircase procedure is used to adjust the ratio to maintain a steady (\~70% correct) level of performance across the trial. The tone matching threshold was calculated at the initial plateau (trials 20-30 during treatment session 1) and at the end of treatment session three. Plasticity Improvement was operationalized as change in threshold from initial plateau to the end of treatment visit 3. Larger (more positive) values represent greater improvement in threshold. Zero would represent no improvement. Values were log transformed.

  At the end of Treatment session 3 (3rd of three sessions)

• Mismatch Negativity (MMN)

  MMN is measured by electroencephalogram (EEG). MMN will be obtained independently to pitch stimuli utilizing the same base frequency as the plasticity task described in outcome 1. MMN was assessed immediately before the first dose and immediately after treatment sessions 2 and 3. MMN will be generated using previously published methods. Peak amplitude at frontocentral electrodes within predefined latency range will be primary outcome measure. This value represents the mean MMN to pitch post baseline (after sessions 2 and 3). More negative represents larger MMN.

  Post baseline

• Theta Intertrial Coherence (Theta)

  Theta is measured by EEG, during the motor-preparation interval (200-500 ms post-the second tone: S2) during the auditory remediation task. Theta inter-trial coherence (ITC) reflects the consistency of spectral response across repeated trials ranging from 0 (no consistency) to 1 (perfect consistency). Higher values represent better consistency.

  Week 1

• Number of Patients With Granular Casts

  This is a safety measure conducted by urinalysis after each D-serine dose. The outcome is the count of participants with granular casts.

  Three weeks

Study Arms (4)

D-serine 80 mg/kg

EXPERIMENTAL

Drug: D-serine

Placebo

PLACEBO COMPARATOR

Drug: Placebo

D-serine 100 mg/kg

EXPERIMENTAL

Drug: D-serine

D-serine 120 mg/g

EXPERIMENTAL

Drug: D-serine

Interventions

D-serine DRUG

Subjects will receive three sessions of auditory remediation paired with either D-serine or Placebo in a 4:1 D-serine:placebo ratio. This will be conducted in 3 separate cohorts of D-serine dose 80, 100 and 120 mg/kg, which 15 subjects per cohort (12 active and 3 placebo) per cohort

D-serine 100 mg/kg; D-serine 120 mg/g; D-serine 80 mg/kg

Placebo DRUG

Subjects will receive three sessions of auditory remediation paired with either D-serine or Placebo in a 4:1 D-serine:placebo ratio. This will be conducted in 3 separate cohorts of D-serine dose 80, 100 and 120 mg/kg, which 15 subjects per cohort (12 active and 3 placebo) per cohort

Placebo

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Age between 18 and 50
• DSM-V diagnosis of schizophrenia or schizoaffective disorder
• Willing to provide informed consent
• Auditory Cognitive impairment demonstrated by:
• a .MCCB composite domain score less than or equal to 0.5 standard deviation below normal (T score less than or equal to 45) b. And at least one of the following:
• MCCB verbal memory domain score less than or equal to 0.5 standard deviation below normal (T score less than or equal to 45)
• Tone matching score of less than or equal to 77.7%
• Clinically stable for 2 months (CGI less than or equal to 4)
• Moderate or lower cognitive disorganization (PANSS P2 less than or equal to 4)
• Medically stable for study participation
• Willing to use qualified methods of contraception for the study duration and up to 2 months after its end
• Fluent English speaker
• Normal hearing
• Visual acuity corrected to 20/30
• An estimated Glomerular Filtration Rate (GFR) greater than or equal to 60

You may not qualify if:

• ECG abnormality that is clinically significant in the context of study participation in the opinion of the study cardiologist
• Current clozapine use
• Presence of positive history of unstable significant medical or neurological illness
• Positive toxicology screen for any substances of abuse
• Substance use disorder (excluding nicotine) within last 60 days
• Pregnant women or women of child-bearing potential, who are either not surgically-sterile or for outpatients, using appropriate methods of birth control. Women of childbearing potential must have a negative serum -hCG pregnancy test at every visit.
• Participation in study of investigational medication/device within 4 weeks
• Subjects with suicidal ideation with intent or plan (indicated by affirmative answers to items 4 or 5 of the Suicidal Ideation section of the baseline C-SSRS) in the 6 months prior to screening or subjects who represent a significant risk of suicide in the opinion of the investigator Section

Sponsors & Collaborators

• New York State Psychiatric Institute: lead
• Nathan Kline Institute for Psychiatric Research: collaborator

Study Sites (2)

New York State Psychiatric Institute

New York, New York, 10032, United States

Location

Nathan Kline Institute

Orangeburg, New York, 10962, United States

Location

Related Publications (3)

• Govani V, Shastry AM, Iosifescu DV, Govil P, Mayer MR, Sobeih T, Choo TH, Wall MM, Sehatpour P, Kantrowitz JT. Augmentation of learning in schizophrenia by d-serine and auditory remediation is related to auditory and frontally-generated biomarkers: A randomized, double-blind, placebo-controlled study. Schizophr Res. 2023 Oct;260:205-208. doi: 10.1016/j.schres.2023.08.027. Epub 2023 Sep 11. No abstract available.

  PMID: 37690312 DERIVED

• Govani V, Shastry A, Iosifescu D, Govil P, Mayer M, Sobeih T, Choo T, Wall M, Sehatpour P, Kantrowitz J. Augmentation of learning in schizophrenia by D-serine is related to auditory and frontally-generated biomarkers: A randomized, double-blind, placebo-controlled study. Res Sq [Preprint]. 2023 May 19:rs.3.rs-2943290. doi: 10.21203/rs.3.rs-2943290/v1.

  PMID: 37293030 DERIVED

• Sehatpour P, Iosifescu DV, De Baun HM, Shope C, Mayer MR, Gangwisch J, Dias E, Sobeih T, Choo TH, Wall MM, Medalia A, Saperstein AM, Kegeles LS, Girgis RR, Carlson M, Kantrowitz JT. 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. Biol Psychiatry. 2023 Jul 15;94(2):164-173. doi: 10.1016/j.biopsych.2023.01.015. Epub 2023 Jan 28.

  PMID: 36958998 DERIVED

MeSH Terms

Conditions

Schizophrenia; Psychotic Disorders

Condition Hierarchy (Ancestors)

Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders

Results Point of Contact

• Title: Dr. Joshua Kantrowitz
• Organization: New York State Psychiatric Institute

Joshua.Kantrowitz@nyspi.columbia.edu

6467746738

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor of Clinical Psychiatry

Study Record Dates

• First Submitted: October 11, 2018
• First Posted: October 18, 2018
• Study Start: March 13, 2019
• Primary Completion: April 30, 2021
• Study Completion: April 30, 2021
• Last Updated: June 14, 2022
• Results First Posted: June 14, 2022

Record last verified: 2022-05

Locations

US (2)