Targeted Vitamin D Treatment of Schizophrenia-Associated Hyperprolinemia

Schizophrenia Clinical Trial

Official title:

Vitamin-D Treatment Targeted to Hyperprolinemia-Associated Schizophrenia.

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT02197286
• Other study ID #: S13-01127
• Status: Withdrawn
• Phase: Phase 2
• First received: July 16, 2014
• Last updated: October 7, 2015
• Start date: February 2015

Study information

• Verified date: October 2015
• Source: New York University School of Medicine
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review BoardUnited States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. primary completion date: December 2017
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 65 Years

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Psychotic Disorders
• Schizoaffective Disorder
• Schizophrenia

Intervention

Drug:
• Cholecalciferol
One capsule containing 4,000 IU of Cholecalciferol, per day
• Placebo
Daily dose of a single gelatin placebo capsule.

Locations

Country	Name	City	State
United States	Bellevue Hospital Center	New York	New York

Sponsors (3)

Lead Sponsor	Collaborator
New York University School of Medicine	Columbia University, Stanley Medical Research Institute

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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.	No
Other	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.	Yes
Other	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.	No
Other	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.	No
Other	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.	No
Primary	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.	No
Secondary	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.	No