Targeted Vitamin D Treatment of Schizophrenia-Associated Hyperprolinemia

NCT ID: NCT02197286

Last Updated: 2015-10-12

Basic Information

• Recruitment Status: WITHDRAWN
• Clinical Phase: PHASE2
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-02-28

Brief Summary

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.

Detailed Description

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.

Conditions

Schizophrenia; Schizoaffective Disorder

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Vitamin D (cholecalciferol)

Intervention: Capsules containing the active ingredient, cholecalciferol @ 4,000 international units (IU). One capsule daily, oral administration for 10 weeks.

Group Type: EXPERIMENTAL

Cholecalciferol

Intervention Type: DRUG

One capsule containing 4,000 IU of Cholecalciferol, per day

Placebo

Daily matching placebo gelatin capsule (also contains microcrystalline cellulose).

Capsules are identical in size, color and taste to experimental drug.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Daily dose of a single gelatin placebo capsule.

Interventions

Cholecalciferol

One capsule containing 4,000 IU of Cholecalciferol, per day

Intervention Type: DRUG

Placebo

Daily dose of a single gelatin placebo capsule.

Intervention Type: DRUG

Other Intervention Names

Other name: Vitamin D3; Trade name:Biotech Pharmacal, Inc: Vitamin D3-4,; 4,000 IU per day

Eligibility Criteria

Inclusion Criteria

1. Male and Female, all racial/ethnic groups, aged 18-65 years.

2. Admission diagnosis of schizophrenia, schizophreniform disorder, or schizoaffective disorder.

3. Capability to give informed consent.

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 disorder.

Exclusion Criteria

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.

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).

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Stanley Medical Research Institute

OTHER

Sponsor Role: collaborator

Columbia University

OTHER

Sponsor Role: collaborator

NYU Langone Health

OTHER

Sponsor Role: lead

Responsible Party

James D. Clelland

Research Assistant Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

James D Clelland

Role: PRINCIPAL_INVESTIGATOR

NYU Langone Health

Locations

Bellevue Hospital Center

New York, New York, United States

Countries

United States

Other Identifiers

S13-01127

Identifier Type: -

Identifier Source: org_study_id