Schizo Affective Disorder, Schizophrenia
Conditions
Keywords
plasticity
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.
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.
Interventions
DRUGD-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
DRUGPlacebo
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
Sponsors
Nathan Kline Institute for Psychiatric Research
New York State Psychiatric Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Plasticity Improvement (Change in Tone Matching Threshold) | At the end of Treatment session 3 (3rd of three sessions) | 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. |
| Mismatch Negativity (MMN) | Post baseline | 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. |
| Theta Intertrial Coherence (Theta) | Week 1 | 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. |
| Number of Patients With Granular Casts | Three weeks | This is a safety measure conducted by urinalysis after each D-serine dose. The outcome is the count of participants with granular casts. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| D-serine 80 mg/kg 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 | 12 |
| Placebo 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 | 9 |
| D-serine 100 mg/kg 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 | 12 |
| D-serine 120 mg/g 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 | 12 |
| Total | 45 |
Baseline characteristics
| Characteristic | D-serine 80 mg/kg | Placebo | D-serine 100 mg/kg | D-serine 120 mg/g | Total |
|---|---|---|---|---|---|
| Age, Continuous | 34.8 years STANDARD_DEVIATION 9.6 | 34.8 years STANDARD_DEVIATION 8 | 37.6 years STANDARD_DEVIATION 6.6 | 35.9 years STANDARD_DEVIATION 8.4 | 35.9 years STANDARD_DEVIATION 8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants | 5 Participants | 6 Participants | 3 Participants | 21 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 4 Participants | 6 Participants | 9 Participants | 24 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United States | 12 Participants | 9 Participants | 12 Participants | 12 Participants | 45 Participants |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 6 Participants | 0 Participants | 9 Participants |
| Sex: Female, Male Male | 11 Participants | 7 Participants | 6 Participants | 12 Participants | 36 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 9 | 0 / 12 | 0 / 12 |
| other Total, other adverse events | 0 / 12 | 0 / 9 | 0 / 12 | 0 / 12 |
| serious Total, serious adverse events | 0 / 12 | 0 / 9 | 0 / 12 | 0 / 12 |
Outcome results
Primary
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.
Time frame: Post baseline
Population: randomized
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| D-serine 80 mg/kg | Mismatch Negativity (MMN) | -1.83 amplitude, micro volts | Standard Deviation 2.1 |
| Placebo | Mismatch Negativity (MMN) | -1.05 amplitude, micro volts | Standard Deviation 1.6 |
| D-serine 100 mg/kg | Mismatch Negativity (MMN) | -2.71 amplitude, micro volts | Standard Deviation 1.7 |
| D-serine 120 mg/g | Mismatch Negativity (MMN) | -0.56 amplitude, micro volts | Standard Deviation 1.5 |
Primary
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.
Time frame: Three weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| D-serine 80 mg/kg | Number of Patients With Granular Casts | 0 Participants |
| Placebo | Number of Patients With Granular Casts | 0 Participants |
| D-serine 100 mg/kg | Number of Patients With Granular Casts | 0 Participants |
| D-serine 120 mg/g | Number of Patients With Granular Casts | 0 Participants |
Primary
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.
Time frame: At the end of Treatment session 3 (3rd of three sessions)
Population: randomized
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| D-serine 80 mg/kg | Plasticity Improvement (Change in Tone Matching Threshold) | 13.9 log ratio | Standard Deviation 17.5 |
| Placebo | Plasticity Improvement (Change in Tone Matching Threshold) | 5.3 log ratio | Standard Deviation 10.8 |
| D-serine 100 mg/kg | Plasticity Improvement (Change in Tone Matching Threshold) | 11 log ratio | Standard Deviation 16.4 |
| D-serine 120 mg/g | Plasticity Improvement (Change in Tone Matching Threshold) | -0.05 log ratio | Standard Deviation 14.1 |
Primary
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.
Time frame: Week 1
Population: randomized
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| D-serine 80 mg/kg | Theta Intertrial Coherence (Theta) | .229 correlation coefficient (r) | Standard Deviation 0.06 |
| Placebo | Theta Intertrial Coherence (Theta) | .241 correlation coefficient (r) | Standard Deviation 0.06 |
| D-serine 100 mg/kg | Theta Intertrial Coherence (Theta) | 0.274 correlation coefficient (r) | Standard Deviation 0.06 |
| D-serine 120 mg/g | Theta Intertrial Coherence (Theta) | .241 correlation coefficient (r) | Standard Deviation 0.07 |