Schizophrenia Clinical Trial
Official title:
Vitamin-D Treatment Targeted to Hyperprolinemia-Associated Schizophrenia.
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.
;
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
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