D-serine Augmentation of Neuroplasticity

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."

Inclusion Criteria:

1. Age between 18 and 50

2. DSM-V diagnosis of schizophrenia or schizoaffective disorder

3. Willing to provide informed consent

4. MCCB composite, attention and verbal memory domain score less than or equal to 1
standard deviation below normal (T score less than or equal to 40)

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