A ten week, blinded trial of vitamin D vs. placebo in 80 patients with schizophrenia or
schizoaffective disorder who have low blood levels of vitamin D and elevated blood levels of
the amino acid proline. The aims of the study are to evaluate an anticipated clinical
response to vitamin D supplementation including negative symptoms and cognitive deficits,
evaluate safety of vitamin D supplementation for schizophrenia patients and evaluate the
relationship of changes in plasma proline levels and efficacy outcomes.
25-hydroxyvitamin D (vitD) insufficiency is associated with cognitive decline and has
long-been considered important in schizophrenia susceptibility. VitD supplementation has
been suggested for those at-risk, and recent studies have demonstrated that vitD
insufficiency extends into both adolescent and adult schizophrenia.
The mechanism by which vitD deficits confers risk is unknown. However, vitD is a
transcriptional regulator, and the investigators recently found that vitD significantly
up-regulates PRODH gene expression. This is important because the highest known genetic risk
of schizophrenia is conferred by hemizygous microdeletion of chromosome 22q11, to which
PRODH maps. Furthermore, PRODH encodes proline oxidase, which catalyzes proline catabolism.
Proline is a neuromodulator at glutamatergic synapses, and peripheral hyperprolinemia has
been associated with learning and memory deficits and neurotransmitter dysregulation in
animal models, and in humans, with decreased intelligence quotient (IQ), cognitive
impairment, and schizoaffective disorder. The investigators recently found that >25% of
schizophrenia patients were hyperprolinemic and hypothesized a causal relationship between
vitD, proline elevation, and schizophrenia, such that vitD insufficiency causes decreased
PRODH expression and hyperprolinemia. Measuring fasting plasma 25hydroxyvitD and proline in
64 patients and 90 controls, the investigators found that vitD insufficiency (<30ng/ml) was
significantly associated with schizophrenia (OR:2.1, p=0.044), vitD levels were negatively
correlated with proline (p=0.01), and vitD insufficient subjects had three times greater
odds of hyperprolinemia (p=0.046). Moreover, they demonstrated that hyperprolinemia explains
>37% of the association between vitD insufficiency and schizophrenia, signifying that vitD
insufficiency increases schizophrenia risk, at least in part by elevating proline. These
findings advocate that targeting schizophrenia-associated hyperprolinemia by alleviating
vitD insufficiency, may improve symptoms including neurocognitive deficits.
The Specific Aims of this study are:
Aim 1) To Evaluate a clinical response to vitamin D3 (vitD3) treatment, targeting patients
with both vitD insufficiency and hyperprolinemia.
Aim 2) To Evaluate the relationship between fasting plasma proline change, PRODH expression,
and symptoms, for development of an efficacy biomarker.
The aims will be accomplished via a ten week, double-blind, placebo controlled trial, in
which schizophrenia or schizoaffective disorder subjects who are both vitD insufficient and
hyperprolinemic, will be randomized to vitD3 (4,000 international units (IU)/day n=40) or
placebo (n=40) as an adjunct to their antipsychotics.
Inclusion Criteria for Recruitment
1. Male and Female, all racial/ethnic groups, aged 18-65 years.
2. Admission diagnosis of schizophrenia, schizophreniform disorder, or schizoaffective
3. Capability to give informed consent.
Inclusion Criteria for Randomization and Trial Entry
1. Fasting hyperprolinemia (defined as 2 standard deviations (SDs) above the
gender-adjusted mean measured for historical controls: 203.3 micromolar (uM) for
females and 327.6 uM for males).
2. 25(OH)D insufficiency (<30ng/ml).
3. Confirmed diagnosis of schizophreniform disorder, schizophrenia or schizoaffective
Exclusion Criteria for Recruitment
1. Organic brain disorders.
2. Valproate treatment within 14 days, because of known proline up-regulatory effects.
3. Pregnant women or women of child-bearing potential, who are not surgically-sterile or
who are not using appropriate methods of birth control.
4. Amino acid metabolism disorder diagnosis.
5. Hypercalcemia (>10.4mg/dL), hypercalciuria (>0.20mg/mg), hyperthyroidism (>65pg/ml)
or history of renal stones, kidney disease, atherosclerosis, sarcoidosis,
histoplasmosis and lymphoma.
6. Chart record of HIV positive status.
7. Treatment with clozapine, as this may reflect general treatment resistance.
Exclusion Criteria for Randomization and Trial Entry
1. Abnormal serum/ urine metabolic lab values suggesting hypercalcemia (serum Calcium
>10.4mg/dL), hypercalciuria (urine calcium/urine creatinine >0.20 mg/mg), or
hyperthyroidism (parathyroid hormone (PTH) > 65pg/ml).
2. Initiation of Valproate treatment.
3. Continued use of dietary supplementation, such as fish oil supplementation or vitamin
D supplements (>400 IU/day).