Kuvan in People With Schizophrenia and Schizoaffective Disorder

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)

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