D-serine Augmentation of Neuroplasticity
Condition: Schizophrenia; Schizo Affective Disorder
MeSH terms: Schizophrenia; Mood Disorders; Psychotic Disorders
Study type: Interventional
Phase: Phase 1/Phase 2

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.
    

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."
    

Intervention name(s): D-serine; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): 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; 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
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: plasticity