Targeted Vitamin D Treatment of Schizophrenia-Associated Hyperprolinemia

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.

Study Overview

• Status: Withdrawn
• Conditions: Schizophrenia; Schizoaffective Disorder
• Intervention / Treatment: Drug: Cholecalciferol; Drug: Placebo

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.

• Study Type: Interventional
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10016
      • Bellevue Hospital Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 61 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

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 disorder.
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 disorder.

Exclusion Criteria:

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Vitamin D (cholecalciferol); Intervention: Capsules containing the active ingredient, cholecalciferol @ 4,000 international units (IU). One capsule daily, oral administration for 10 weeks.	Drug: Cholecalciferol; One capsule containing 4,000 IU of Cholecalciferol, per day; Other Names: Other name: Vitamin D3; Trade name:Biotech Pharmacal, Inc: Vitamin D3-4,; 4,000 IU per day
Placebo Comparator: Placebo; Daily matching placebo gelatin capsule (also contains microcrystalline cellulose). Capsules are identical in size, color and taste to experimental drug.	Drug: Placebo; Daily dose of a single gelatin placebo capsule.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical response to supplementation with vitamin D.	To evaluate an anticipated clinical response to supplementation with vitamin D including negative symptoms and cognitive deficits by the change in the Positive and Negative Symptom Scale (PANSS) total score and the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) consensus cognitive scale. Secondary outcomes will also involve investigation of individual domains of the PANSS and MATRICS.	Baseline (start of vitamin D supplementation) through ten weeks of treatment.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Biological response to supplementation with vitamin D.	Measure plasma proline levels and peripheral PRODH gene expression levels, and examine the relationship with clinical symptoms and cognitive deficits for efficacy biomarker development.	Lead-in phase visit, baseline visit and then at biweekly visits through ten weeks of treatment.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Length of hospital stay.	Firstly, compare the length of hospitalization between study arms. Secondly, measure plasma proline levels and peripheral gene expression, and examine the relationship via regression modeling, with the length of hospitalization.	Lead-in phase visit, baseline visit and then at biweekly visits until discharge, an expected average period from lead-in to discharge of seven weeks.
Number of participants with adverse events as a measure of safety.	To evaluate the safety of vitamin D supplementation for schizophrenic or schizoaffective patients, by collecting data on all adverse events.	Throughout 10 week treatment study period.
Clinical response to supplementation with vitamin D.	To evaluate a clinical response to vitamin D supplementation by the change in the Brief Ratings Psychiatric Scale.	Baseline (start of vitamin D supplementation) through ten weeks of treatment.
Clinical response to supplementation with vitamin D.	To evaluate a clinical response to vitamin D supplementation by the change in the Wechsler Adult Intelligence scale.	Baseline (start of vitamin D supplementation) through ten weeks of treatment.
Clinical response to supplementation with vitamin D.	To evaluate a clinical response to vitamin D supplementation by the change in the Clinical Global Impression scale.	Baseline (start of vitamin D supplementation) through ten weeks of treatment.

Collaborators and Investigators

• Sponsor: NYU Langone Health
• Collaborators: Columbia University; Stanley Medical Research Institute
• Investigators: Principal Investigator: James D Clelland, NYU Langone Health

Study record dates

Study Major Dates

• Study Start: February 1, 2015
• Primary Completion (Anticipated): December 1, 2017

Study Registration Dates

• First Submitted: July 16, 2014
• First Submitted That Met QC Criteria: July 18, 2014
• First Posted (Estimate): July 22, 2014

Study Record Updates

• Last Update Posted (Estimate): October 12, 2015
• Last Update Submitted That Met QC Criteria: October 7, 2015
• Last Verified: October 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Schizophrenia Spectrum and Other Psychotic Disorders; Schizophrenia; Psychotic Disorders; Physiological Effects of Drugs; Micronutrients; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Vitamin D; Cholecalciferol; Vitamins; Ergocalciferols
• Other Study ID Numbers: S13-01127