Schizoaffective Disorder, Schizophrenia
Conditions
Keywords
biomarker, EEG, schizophrenia, NMDA, D-serine
Brief summary
N-methyl-D-aspartate (NMDA)-type glutamate receptors are thought to play a pivotal role in neurocognitive dysfunction associated with schizophrenia. Further, several novel glutamate-based classes of compound are presently in development as potential novel treatments for persistent negative and cognitive symptoms. The study will assess effectiveness of a NMDA-based intervention on biomarkers related to schizophrenia as a mechanism for developing appropriate outcome batteries for future trials of novel compounds.
Detailed description
16 in- or outpatients with DSM-IV-TR schizophrenia or schizoaffective disorder and prominent negative symptoms will be recruited for this study. This study will consist of a randomized trial of D-serine (60 mg/kg/d) vs. placebo using a crossover design with a 2-week baseline lead-in, and two 6-week intervention arms separated by a two week, placebo controlled washout period. Biomarkers will be assessed at baseline for each treatment arm, acutely (day 7) following treatment initiation, and following 6 weeks of treatment (6 biomarker sessions total). Primary biomarker outcome measures will include 1) amplitude of the mismatch negativity (MMN) waveform and 2) amplitude of the visual P1 potential. Symptomatic outcome measures will include PANSS and composite score of the MATRICS neuropsychological battery. The study will be supported from ongoing NIMH-funded Cooperative Drug Development Grant (CDDG) to the PI.
Interventions
DRUGD Serine
60 mg/kg/day
DRUGPlacebo
oral
Sponsors
Nathan Kline Institute for Psychiatric Research
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 64 Years
Healthy volunteers
No
Inclusion criteria
* Age 18-64 * SCID diagnosis of Schizophrenia or Schizoaffective Disorder. * PANSS 3 factor negative symptom (screening and baseline visit 1 and visit 3) score of \>20 and PANSS total score between 60-110. Any degree of positive symptoms is acceptable but the total PANSS score must not exceed 110. * SAS total score less than or equal to 12 and a Calgary Depression Inventory total score less than or equal to 10 and suicide (item 8) less than moderate (\<2). * Two consecutive CGI ratings at screening and baseline (visit 1 and 3) with no change in score. * Estimated Glomerular Filtration Rate (GFR)(a measure of renal function) greater than or equal to 60.
Exclusion criteria
* Organic brain disorder, including epilepsy; mental retardation; or a medical condition whose pathology or treatment would likely alter the presentation or treatment of schizophrenia or significantly increase the risk associated with any of the proposed treatments * Current DSM-IV diagnosis of drug/alcohol abuse in last month and current DSM-IV diagnosis of drug/alcohol dependence in last 6 months * Pregnant female patients * Impaired renal function * Significant extrapyramidal symptoms (as reflected by a total score of 10 or above on the SAS scale), and depressive symptoms (as reflected by a score of 10 or above on the Calgary Depression Scale for Schizophrenia) * Patients who are unable to or unwilling to participate in the Cognitive assessment (MATRICS) and the electrophysiology tasks . * Patients on clozapine
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| PANSS Total | 6 weeks | Positive and Negative Symptom Scale (PANSS) range 30-210 |
| MMN Amplitude | 6 weeks | Final MMN amplitude |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| MATRICS | 6 weeks | MATRICS assessing 7 domains (Speed of Processing, Attention/Vigilance, Working Memory, Verbal Learning, Visual Learning, Reasoning and Problem Solving, and Social Cognition. Raw scores are converted into a composite T-score (normative mean = 50; standard deviation = 10), where higher values indicated less impairment. |
| Visual P1 | 6 weeks | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| D-serine Followed by Placebo Does not include 1 drop-out during phase 1 | 7 |
| Placebo Followed by D-serine Does not include 1 drop-out during phase 1 | 7 |
| Total | 14 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | D-serine Followed by Placebo | Placebo Followed by D-serine | Total |
|---|---|---|---|
| Age, Continuous | 36 years STANDARD_DEVIATION 10 | 44.6 years STANDARD_DEVIATION 11 | 40 years STANDARD_DEVIATION 11 |
| Chlorpromazine equivalents | 1135 mg STANDARD_DEVIATION 967 | 795 mg STANDARD_DEVIATION 496 | 965 mg STANDARD_DEVIATION 760 |
| In-patient number | 6 Participants | 4 Participants | 10 Participants |
| PANSS total | 83.7 units on a scale STANDARD_DEVIATION 9 | 80.1 units on a scale STANDARD_DEVIATION 10 | 80.8 units on a scale STANDARD_DEVIATION 8.4 |
| Sex: Female, Male Female | 1 Participants | 0 Participants | 1 Participants |
| Sex: Female, Male Male | 6 Participants | 7 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 0 / 16 |
| serious Total, serious adverse events | 0 / 16 |
Outcome results
Primary
MMN Amplitude
Final MMN amplitude
Time frame: 6 weeks
Population: Includes 11 subjects with analyzable MMN data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| D-serine | MMN Amplitude | -1.21 micro volts | Standard Deviation 0.6 |
| Placebo | MMN Amplitude | -.21 micro volts | Standard Deviation 0.9 |
p-value: 0.001Mixed Models Analysis
Primary
PANSS Total
Positive and Negative Symptom Scale (PANSS) range 30-210
Time frame: 6 weeks
Population: Final score end of six weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| D-serine | PANSS Total | 77.9 units on a scale | Standard Deviation 9.3 |
| Placebo | PANSS Total | 80 units on a scale | Standard Deviation 10.3 |
p-value: 0.02Mixed Models Analysis
Secondary
MATRICS
MATRICS assessing 7 domains (Speed of Processing, Attention/Vigilance, Working Memory, Verbal Learning, Visual Learning, Reasoning and Problem Solving, and Social Cognition. Raw scores are converted into a composite T-score (normative mean = 50; standard deviation = 10), where higher values indicated less impairment.
Time frame: 6 weeks
Population: Final score after six weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| D-serine | MATRICS | 26.2 T score | Standard Deviation 7.6 |
| Placebo | MATRICS | 25.7 T score | Standard Deviation 7.9 |
p-value: 0.31Mixed Models Analysis
Secondary
Visual P1
Time frame: 6 weeks
Population: includes subjecst with valid visual p1 data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| D-serine | Visual P1 | -.21 micro volts | Standard Deviation 1.3 |
| Placebo | Visual P1 | -.54 micro volts | Standard Deviation 1.2 |
p-value: 0.41Mixed Models Analysis