Schizophrenia Prodrome
Conditions
Keywords
schizophrenia, d-serine, prodrome
Brief summary
The purpose of the study is to determine the safety and efficacy of D-serine as an early intervention treatment for the schizophrenia prodrome condition. This study is a placebo-controlled trial of D-serine in the symptomatic treatment of patients with the schizophrenia prodrome. Seventy two subjects meeting criteria for the schizophrenia prodrome will be included in this study, 24 at each site (Yale, Nathan Kline Institute and Zucker Hillside Hospital). The primary outcome measures will include symptom and neuropsychological measures. The duration of this study is two and a half years. This research with D-serine holds out the prospect of direct benefit for the patient's current symptoms. Subjects may also benefit from the close monitoring of their symptoms, so that, if schizophrenic psychosis does occur, the psychosis will be recognized and treatment may begin with minimal delay. This study also could be of benefit by suggesting a promising lead in early intervention in the schizophrenic prodrome. Overall Design Summary. We propose for prodromal patients to be randomized to D-serine vs placebo for 16 weeks. To insure that all subjects have the opportunity to receive D-serine, there will be an optional 16 week cross-over trial on the alternate study medication. No subject will be on D-serine for longer than 16 weeks. Admission criteria, Assessment Procedures, and Study Design will be the same across all sites. The procedures and timeline are shown in Table 1. The procedures and timeline are the same for the initial randomized 16 week trial and the optional cross-over trial on the alternate study medication. If patient's opt for the 16 week treatment on the alternate medication, we will use their assessments from end of initial treatment as baseline for 16 week treatment on alternate medication. Subjects will be seen for two preliminary visits, then once in treatment, subjects will be seen weekly for the first 5 visits then biweekly thereafter. A safety blood and urine collection will be done on day 3 (3 days after the start of study medication). Vital signs and weight, blood draw and urine collection for safety measures, urine pregnancy test and urine for toxicology will be repeated throughout treatment. Adverse effects ratings and symptom assessments will be repeated at each visit. Neuropsychological assessment and optional Biomarker study visual, auditory and ERPs tasks will be administered during one of the two preliminary visits then again at study endpoint. Any patients who convert to frank psychosis will be referred/offered immediate treatment.
Interventions
DRUGD-serine
60 mg/kg/day
OTHERPlacebo
Inert Placebo
Sponsors
Yale University
The Zucker Hillside Hospital
National Institute of Mental Health (NIMH)
Nathan Kline Institute for Psychiatric Research
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
13 Years to 35 Years
Healthy volunteers
No
Inclusion criteria
1. treatment seeking subjects ages 13-35 who meet criteria for the schizophrenia prodrome (see criteria below) and who are able to give written informed assent or consent. 2. Subjects must score at least 20 on the Scale of Prodromal Symptoms (SOPS) total score at visit -1. 3. Patients may be receiving ongoing treatment with antipsychotic, antidepressant or anti-anxiety medications as prescribed by their treating physician, or may be medication free. 4. Patients may enroll in the treatment phase only if they have been on fixed medication dosage for at least 4 weeks. If possible, medication will be held constant during course of study. Subjects will not be excluded or dropped from the study if they have a psychiatric diagnosis or must start a new medication unless the diagnosis is psychosis. Medication changes and increases or decreases in medication will be permitted at the discretion of the treating physician, and, if they occur, will be treated as secondary outcome measures.
Exclusion criteria
1. inability to give informed assent or consent, 2. history of psychosis (e.g. frank delusions, hallucinations, or thought disorder), 3. psychotropic medication begun or dose adjusted within 4 weeks of visit 0, 4. contraindication to study medication, 5. inclusion symptoms better accounted for by comorbid diagnosis, 6. treatment need for comorbid diagnosis outweighs that for prodromal symptoms, 7. unstable medical illness, 8. females who are of childbearing potential but are not taking adequate contraceptive precautions or who are pregnant or breast feeding, 9. alcohol or drug abuse or dependence in the past three months, 10. either of the following: Subjects with significant renal disease or estimated GFR below 60 (MDRD, http://www.kidney.org/professionals/kdoqi/gfr\_calculator.cfm) will be excluded (see below for details). Any subject taking or unwilling to avoid other nephrotoxic agents during the course of the study (NSAIDS, ACE inhibitors, ARB's, calcineurin inhibitors, or aminoglycosides) will also be excluded. Therefore, patients will be asked during the study to take acetaminophen (e.g. if they have a headache) and to avoid taking ibuprofen. For adolescents (ages 13-17), more stringent renal
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Scale of Prodromal Symptoms (SOPS) Negative Scale | 16 weeks | The SOPS Negative symptom scale consists of six Negative Symptom items. Each item has a severity scale rating from 0 (Never, Absent) to 6 (Severe/Extreme). The severity of the prodromal state is judged according to the sum of the ratings from each of the SOPS items and ranges from 0 to 36. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Scale of Prodromal Symptoms (SOPS) Total | 16 weeks | The SOPS Total consists of five Positive Symptom items, six Negative Symptom items, four Disorganization Symptom items, and four General Symptom items. Each item has a severity scale rating from 0 (Never, Absent) to 6 (Severe/Extreme-and Psychotic, for the positive items). The severity of the prodromal state is judged according to the sum of the ratings from each of the SOPS items and ranges from 0 to 114. |
| IL6 Levels | 16 weeks | Final IL6 levels (pg/ml) in available subjects |
| Pittsburgh Sleep Quality Index Score | 16 weeks | The Pittsburgh Sleep Quality Index (PSQI) consists of 19 self-rated questions and five questions rated by the bed partner or roommate. The latter five questions are used for clinical information only, are not tabulated in the scoring of the PSQI. The 19 self-rated questions assess a wide variety of factors relating to sleep quality, including estimates of sleep duration and latency and of the frequency and severity of specific sleep-related problems. These I9 items are grouped into seven component scores, each weighted equally on a 0-3 scale. The seven component scores are then summed to yield a global PSQI score, which has a range of 0-21; higher scores |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| D Serine 60 mg/kg/day
D-serine: 60 mg/kg/day | 15 |
| Placebo Placebo: Inert Placebo | 20 |
| Total | 35 |
Baseline characteristics
| Characteristic | Placebo | D Serine | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 9 Participants | 7 Participants | 16 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 11 Participants | 8 Participants | 19 Participants |
| Age, Continuous | 19 years STANDARD_DEVIATION 3.5 | 20 years STANDARD_DEVIATION 4.9 | 19.5 years STANDARD_DEVIATION 4.1 |
| Region of Enrollment United States | 20 participants | 15 participants | 35 participants |
| Sex: Female, Male Female | 5 Participants | 7 Participants | 12 Participants |
| Sex: Female, Male Male | 15 Participants | 8 Participants | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 2 / 20 | 0 / 24 |
| serious Total, serious adverse events | 1 / 20 | 0 / 24 |
Outcome results
Primary
Scale of Prodromal Symptoms (SOPS) Negative Scale
The SOPS Negative symptom scale consists of six Negative Symptom items. Each item has a severity scale rating from 0 (Never, Absent) to 6 (Severe/Extreme). The severity of the prodromal state is judged according to the sum of the ratings from each of the SOPS items and ranges from 0 to 36.
Time frame: 16 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| D Serine | Scale of Prodromal Symptoms (SOPS) Negative Scale | 7.6 SOPS negative final score | Standard Deviation 1.4 |
| Placebo | Scale of Prodromal Symptoms (SOPS) Negative Scale | 11.3 SOPS negative final score | Standard Deviation 1.2 |
p-value: 0.03Mixed Models Analysis
Secondary
IL6 Levels
Final IL6 levels (pg/ml) in available subjects
Time frame: 16 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| D Serine | IL6 Levels | .49 final IL6 level (pg/ml)) | Standard Deviation 0.25 |
| Placebo | IL6 Levels | .79 final IL6 level (pg/ml)) | Standard Deviation 0.52 |
p-value: 0.056t-test, 2 sided
Secondary
Pittsburgh Sleep Quality Index Score
The Pittsburgh Sleep Quality Index (PSQI) consists of 19 self-rated questions and five questions rated by the bed partner or roommate. The latter five questions are used for clinical information only, are not tabulated in the scoring of the PSQI. The 19 self-rated questions assess a wide variety of factors relating to sleep quality, including estimates of sleep duration and latency and of the frequency and severity of specific sleep-related problems. These I9 items are grouped into seven component scores, each weighted equally on a 0-3 scale. The seven component scores are then summed to yield a global PSQI score, which has a range of 0-21; higher scores
Time frame: 16 weeks
Population: Completers at NYSPI and NKI sites
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| D Serine | Pittsburgh Sleep Quality Index Score | 4 final score | Standard Deviation 2.9 |
| Placebo | Pittsburgh Sleep Quality Index Score | 7.7 final score | Standard Deviation 3.5 |
p-value: 0.12Mixed Models Analysis
Secondary
Scale of Prodromal Symptoms (SOPS) Total
The SOPS Total consists of five Positive Symptom items, six Negative Symptom items, four Disorganization Symptom items, and four General Symptom items. Each item has a severity scale rating from 0 (Never, Absent) to 6 (Severe/Extreme-and Psychotic, for the positive items). The severity of the prodromal state is judged according to the sum of the ratings from each of the SOPS items and ranges from 0 to 114.
Time frame: 16 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| D Serine | Scale of Prodromal Symptoms (SOPS) Total | 23.9 units on a scale | Standard Deviation 2.8 |
| Placebo | Scale of Prodromal Symptoms (SOPS) Total | 30.5 units on a scale | Standard Deviation 2.4 |
p-value: 0.07Mixed Models Analysis