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D-serine Augmentation of Neuroplasticity

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03711500
Recruitment Status : Suspended (This study is temporarily suspended due to COVID-19 pandemic.)
First Posted : October 18, 2018
Last Update Posted : April 20, 2020
Sponsor:
Collaborator:
Nathan Kline Institute for Psychiatric Research
Information provided by (Responsible Party):
Joshua Kantrowitz, New York State Psychiatric Institute

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.


Condition or disease Intervention/treatment Phase
Schizophrenia Schizo Affective Disorder Drug: D-serine Drug: Placebo Phase 1 Phase 2

Detailed Description:

Schizophrenia (Sz) is a major public health problem associated with core cognitive deficits that are amongst the strongest predictors of impaired functional outcome. In addition, Sz patients show reduced cortical neuroplasticity, defined as reduced learning during training on exercises that place implicit, increasing demands on early auditory information processing. As improved auditory processing can facilitate gains in those cognitive processes that are more proximal to daily functioning (e.g., verbal memory, executive functioning), enhancing neuroplasticity for better auditory processing represents an unmet clinical need and a rate-limiting first step prior to remediating cognition and overall function.

As supported by recently published data and review, the study proposes that localized N-methyl-D-aspartate-type glutamate receptor (NMDAR) dysfunction leads to impaired auditory neuroplasticity, which in turn leads to impaired cognition. Over recent years, NMDAR glycine site agonists have increasingly been shown to facilitate neuroplasticity in both Sz and healthy volunteers.

D-serine is a NMDAR modulator that when combined with neuroplasticity-based auditory remediation, leads to highly significant, acute improvement in both auditory plasticity and the early auditory processing measures mismatch negativity (MMN) and theta intertrial coherence (theta). Both MMN and theta-ITC are sensitive measures of functional target engagement of both NMDAR agonism and auditory remediation. In a preliminary study, plasticity correlated with reading and working memory, suggesting plasticity improvements are predictive of functionally relevant outcomes. While D-serine appears to be efficacious for neuroplasticity enhancement and target engagement in a dose dependent manner, the optimal dose remains an open question, as does the ability of combined D-serine + neuroplasticity-based auditory remediation to produce sustained, functional improvement. This study utilizes the Early Stage Testing of Pharmacologic or Device-based Interventions for the Treatment of Mental Disorders (R61/R33): RFA-MH-17-702.

The ultimate goal of this study is to enhance efficacy and efficiency of auditory cognitive remediation by augmenting with D-serine. This study will confirm target engagement, pharmacodynamics, functional relationships and the optimal dose (80 vs.100 vs. 120 mg/kg, IND: 122821) of D-serine treatment combined with 3 sessions of our auditory remediation program. As previously, D-serine will be given 30 minutes before sessions, allowing for auditory remediation during peak serum levels and a pharmacodynamic assessment. Successful completion is defined by ≥moderate effect size change in auditory plasticity, MMN and theta, plus a moderate effect size correlation with functionally relevant cognitive measures ("auditory cognition") without safety issues. Successful completion of this study will pave the way for a larger, definitive study pairing D-serine with auditory remediation or testing alternative dose intervals (1x vs. 2x week). In addition to testing a potentially viable treatment, this project will stimulate industry to utilize this methodology to assess the efficacy of novel NMDAR modulators, using D-serine as a "gold-standard."

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 45 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: D-serine Augmentation of Neuroplasticity Based Auditory Learning in Schizophrenia
Actual Study Start Date : March 13, 2019
Estimated Primary Completion Date : December 2020
Estimated Study Completion Date : December 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Schizophrenia
Drug Information available for: Serine

Arm Intervention/treatment
Experimental: D-serine Drug: D-serine
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 Comparator: Placebo Drug: Placebo
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




Primary Outcome Measures :
  1. Tone matching threshold (plasticity) [ Time Frame: Three weeks ]
    This is the outcome of the 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. Ratios in each pair are log-transformed and averaged across 10-trial pairs (e.g., pairs 1-10, 11-20, etc.).

  2. Mismatch negativity (MMN) [ Time Frame: Three weeks ]

    MMN is measured by electroencephalogram (EEG). MMN will be obtained independently to pitch stimuli utilizing the same base frequencies as the plasticity task described in outcome 1. Two sessions will be held each day, both before and after study drug/auditory remediation intervention. MMN will be generated using previously published methods. Peak amplitude at frontocentral electrodes within predefined latency range will be primary outcome measure. We primarily evaluate effect of study drug.

    pre-post auditory remediation.


  3. Theta Intertrial coherence (theta) [ Time Frame: Three weeks ]
    Theta is measured by EEG. Theta will be measured during the auditory remediation over predefined latency.

  4. Number of Granular casts [ Time Frame: Three weeks ]
    This is a safety measure conducted by urinalysis after each D-serine dose. The outcome is the number of granular casts



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 50 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age between 18 and 50
  2. DSM-V diagnosis of schizophrenia or schizoaffective disorder
  3. Willing to provide informed consent
  4. 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%
  5. Clinically stable for 2 months (CGI less than or equal to 4)
  6. Moderate or lower cognitive disorganization (PANSS P2 less than or equal to 4)
  7. Medically stable for study participation
  8. Willing to use qualified methods of contraception for the study duration and up to 2 months after its end
  9. Fluent English speaker
  10. Normal hearing
  11. Visual acuity corrected to 20/30
  12. An estimated Glomerular Filtration Rate (GFR) greater than or equal to 60
  13. Taking an antipsychotic medication other than clozapine at a stable dose for at least 4 weeks
  14. Judged clinically not to be at significant suicide or violence risk

Exclusion Criteria:

  1. ECG abnormality that is clinically significant in the context of study participation in the opinion of the study cardiologist
  2. Current clozapine use
  3. Presence of positive history of unstable significant medical or neurological illness
  4. Positive toxicology screen for any substances of abuse
  5. Substance use disorder (excluding nicotine) within last 60 days
  6. 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.
  7. Participation in study of investigational medication/device within 4 weeks
  8. 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03711500


Locations
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United States, New York
New York State Psychiatric Institute
New York, New York, United States, 10032
Nathan Kline Institute
Orangeburg, New York, United States, 10962
Sponsors and Collaborators
New York State Psychiatric Institute
Nathan Kline Institute for Psychiatric Research
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Responsible Party: Joshua Kantrowitz, Assistant Professor of Clinical Psychiatry, New York State Psychiatric Institute
ClinicalTrials.gov Identifier: NCT03711500    
Other Study ID Numbers: 7725
First Posted: October 18, 2018    Key Record Dates
Last Update Posted: April 20, 2020
Last Verified: April 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Joshua Kantrowitz, New York State Psychiatric Institute:
plasticity
Additional relevant MeSH terms:
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Schizophrenia
Mood Disorders
Psychotic Disorders
Schizophrenia Spectrum and Other Psychotic Disorders
Mental Disorders