Schizophrenia, Schizoaffective Disorder
Conditions
Brief summary
Rater blinded trial of six weeks of Kuvan vs. multivitamin in 60 outpatients with schizophrenia or schizoaffective disorder. The aims are to evaluate an anticipated clinical response to Kuvan treatment including negative symptom and cognitive deficits, evaluate safety of Kuvan treatment for schizophrenic patients and evaluate the relationship of changes in plasma Kuvan levels and efficacy outcomes.
Detailed description
Tetrahydrobiopterin (BH4) is a vital central nervous system (CNS) cofactor that maintains availability of amine neurotransmitters such as dopamine (DA) and serotonin (5HT), and stimulates and modulates the glutamatergic system. Dysregulation of these neurotransmitter systems has been implicated in the pathogenesis of schizophrenia (SZ). A central role of BH4 in schizophrenia is further supported by a study finding a relative deficit of 32% for SZ patients as compared to controls. The observed BH4 deficit is comparable to that reported for genetic BH4 deficiency disorders, supporting its characterization as having physiological significance. This highly significant finding, along with: a) the known roles of BH4 in neurotransmitter maintenance, b) dysregulation of CNS neurotransmitter synthesis observed in human BH4 deficiencies, c) evidence that plasma biopterin levels are correlated with CNS biopterin levels, and d) evidence that urinary biopterin excretion is not increased in SZ, all support our hypothesis that dysregulation of BH4 biosynthesis is involved in the pathophysiology of SZ. Moreover, additional data suggesting that mood stabilizer drugs can moderately increase levels of biopterin in patients with psychiatric disorders, and the reported efficacy of BH4 in pilot studies of neuropsychiatric disorders, suggest that alleviation of the schizophrenia BH4 deficit via treatment with synthetic BH4 supplement (Sapropterin dihydrochloride or Kuvan), may give rise to an improvement of the symptoms of schizophrenia, including positive and negative symptoms as well as neurocognitive deficits. Sapropterin dihydrochlorides, teh active pharmaceutical ingredient in Kuvan Tablets,is a synthetic preparation of the dihydrochloride salt of naturally occurring tetrahydrobiopterin (BH4)
Interventions
DRUGKuvan
20mg/kg using a daily dosing schedule. To increase tolerability, treatment will be initiated at 10mg/kg for the first week of the study. Given the short length of the trial, no dose adjustments will be made for changes in weight
DRUGMultivitamin
Multi-vitamin will be used as an active control in this study. Will be dosed daily
Sponsors
Stanley Medical Research Institute
New York State Psychiatric Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 64 Years
Healthy volunteers
No
Inclusion criteria
* Male and female outpatients with schizophrenia or schizoaffective disorder * Ages 18-64 * A score of 45 or greater on PANSS * All oral and depot antipsychotics (with the exception of clozapine) are allowable. Patients must be on their antipsychotic medication for 3 months and stable on dose of antipsychotic and adjunctive medications for 2 weeks prior to study entry. If a patient is on depot medication, they must be stable in dose for 2 months
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 * Participated in any investigational study or taken an investigational drug within 30 days * Current Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) diagnosis of drug/alcohol abuse in last month and current DSM-IV diagnosis drug/alcohol dependence in last 6 months. Subjects must have a negative drug screen at baseline (with one retest allowed for suspected false positive based on clinical judgement of the investigator) * Diagnosis of any known BH4 deficiency disorder (other than schizophrenia or schizoaffective disorder), including dopa-responsive dystonia,phenylketonuria (PKU), and autism * Current treatment with clozapine * In the investigator's judgment, a significant risk of suicide or violent behavior * Current use of levodopa and nitric oxide-mediated vasorelaxation or oral minoxidil * Women will be excluded if they are pregnant, lactating, or not either surgically-sterile or using appropriate methods of birth control. Women must agree to continue using applicable birth control throughout the trial. All women of child-bearing potential must have a negative urine pregnancy test at the screening visit and visit 2 (1 week before beginning study medication) * Absolute neutrophil count below 2.0 on screening * Any contraindication or allergic reaction to previous multi-vitamin or unwillingness to stop use of current multi-vitamin during study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Final Positive and Negative Symptom Scale (PANSS) | Baseline (start of Kuvan) and at six weeks of treatment | This is a is a 30 item rating scale widely used in the assessment of schizophrenia ranging from 30-210. Higher scores are worse |
| Final MATRICS Cognitive Battery | Baseline to week 6 | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Kuvan Kuvan once-daily dosing initiated with 10mg/kg for the first week followed by 20mg/kg for the remaining weeks of the study
Kuvan: 20mg/kg using a daily dosing schedule. To increase tolerability, treatment will be initiated at 10mg/kg for the first week of the study. Given the short length of the trial, no dose adjustments will be made for changes in weight | 13 |
| Multivitamin Daily multivitamin tablet
Multivitamin: Multi-vitamin will be used as an active control in this study. Will be dosed daily | 12 |
| Total | 25 |
Baseline characteristics
| Characteristic | Multivitamin | Total | Kuvan |
|---|---|---|---|
| Age, Continuous | 46.1 years STANDARD_DEVIATION 8 | 43.0 years STANDARD_DEVIATION 10.1 | 40.15 years STANDARD_DEVIATION 12.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 5 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 11 Participants | 20 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 13 Participants | 8 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 9 Participants | 3 Participants |
| Sex: Female, Male Female | 3 Participants | 8 Participants | 5 Participants |
| Sex: Female, Male Male | 9 Participants | 17 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 8 / 13 | 9 / 12 |
| serious Total, serious adverse events | 0 / 13 | 0 / 12 |
Outcome results
Primary
Final MATRICS Cognitive Battery
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: Baseline to week 6
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Kuvan | Final MATRICS Cognitive Battery | 33.92 Total MATRICS score | Standard Deviation 17.1 |
| Multivitamin | Final MATRICS Cognitive Battery | 35.0 Total MATRICS score | Standard Deviation 12.5 |
p-value: 0.99ANOVA
Primary
Final Positive and Negative Symptom Scale (PANSS)
This is a is a 30 item rating scale widely used in the assessment of schizophrenia ranging from 30-210. Higher scores are worse
Time frame: Baseline (start of Kuvan) and at six weeks of treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Kuvan | Final Positive and Negative Symptom Scale (PANSS) | 54.4 PANSS Total | Standard Deviation 10.9 |
| Multivitamin | Final Positive and Negative Symptom Scale (PANSS) | 60.2 PANSS Total | Standard Deviation 13.7 |
Comparison: Univariate ANOVA, controlling for baseline PANSS totalp-value: 0.38ANOVA